ES2838625T3 - Amide derivatives and pharmaceutically acceptable salts thereof, their method of preparation and medical application thereof - Google Patents

Abstract

A compound of general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof: ** (See formula) ** where: the ring P is selected from a five-membered heteroaryl and a five-membered heterocyclyl; ring Q is selected from phenyl and pyridinyl; A, B or Y is selected from -CH- and N; R1 is selected from alkyl and cycloalkyl, wherein said alkyl or cycloalkyl is furthermore optionally substituted by one or more groups selected from the group consisting of alkyl, halogen and haloalkyl; R2 is selected from halogen and haloalkyl; R3 are identical or different, and each is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, and oxo, wherein said alkyl, cycloalkyl, and heterocyclyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, alkoxy, and alkyl; R4 is selected from phenyl and pyridinyl, wherein said phenyl and pyridinyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein said haloalkyl is preferably trifluoromethyl; s is an integer between 0 to 3; t is 1.

Description

DESCRIPTION

Amide derivatives and pharmaceutically acceptable salts thereof, their method of preparation and medical application thereof

Field of the invention

The present invention relates to new amide derivatives, a method of preparing them and pharmaceutical compositions containing them, as well as their use as a therapeutic agent, especially as an inhibitor of microsomal prostaglandin E synthase 1 (mPGES- 1), and to the use thereof in the preparation of a medicament for the treatment and / or prevention of diseases or disorders such as inflammation and / or pain, etc.

Background of the invention

Many diseases and / or disorders are essentially inflammatory. A major existing problem associated with the treatment of inflammatory diseases is the lack of efficacy and / or the presence of common side effects. Inflammatory diseases involved in humans include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis, dermatitis, and the like. Inflammation is a common cause of pain, which can be due to a variety of reasons, such as infection, surgery, or other injuries. On the other hand, some diseases, including a malignant tumor and cardiovascular disease, also have the symptoms of inflammation.

Prostaglandin E2 (prostaglandin E2, PGE2) is one of the most common prostaglandins (PG), which is a strong pro-inflammatory mediator and can induce fever and pain, participates in a variety of physiological and pathological processes in the body. Its chemical synthesis consists of three consecutive enzymatic reactions: (1) arachidonic acid (AA) is released from glycerophospholipid in the membranes through the catalysis of phospholipase A2 (PLA2); (2) AA generates PGg 2 and PGH2 by the action of cyclooxygenase (COX); (3) PGH2 generates PGE2, PGF2, pGD2, prostacillin and thromboxane A2 by catalysis of PGE2 synthase (PGES).

There are two forms of cyclooxygenase (COX). One is constitutively expressed as COX-1 in many of the cells and tissues, and the other is COX-2, induced by a pro-inflammatory stimulus such as cytokines during an inflammatory reaction. Currently, there are types of COX-1 and / or COX-2 inhibitors to control inflammation by reducing the final formation of PGE2, such as "NSAIDs" (non-steroidal anti-inflammatory drug) and "coxib" (inhibitor selective for cox-2). However, inhibition of target COX will reduce the generation of all metabolites from arachidonic acid (AA), including some metabolites that are beneficial to the human body. Therefore, COX inhibitors can cause adverse biological effects to the human body. Therefore, the development of a new, safer and more effective drug for inflammatory diseases is of great clinical importance and market value.

PGES that targets PGE2 synthesis is a terminal rate-limiting enzyme during the PGE2 synthesis process. As is well known, there are at least three types of PGES, called cytoplasmic PGES (cPGES) (or called PGE-3), membrane-bound PGES-1 (mPGES-1), and membrane-bound Pg ES-2 (mPGES-2 ). CPGES is a GSH-dependent constitutive enzyme, which is an enzyme that is widely expressed by housekeeping genes in multiple tissues and cells, and is unaffected by an inflammation-stimulating factor. MPGES-2 is a constitutive enzyme independent of GSH, which is expressed mainly in tissues with a relatively low expression of mPGES-1, such as brain, heart, kidney, intestine, and is not induced by inflammation and tissue damage. MPGES-1 is a GSH-dependent inducible expression enzyme, which can be expressed largely due to induction by an inflammatory factor and plays an important role in a variety of diseases, such as arthritis, fever and pain associated with inflammation, atherosclerosis and pathological and physiological processes of cancer. The mPGES-1 gene is on chromosome 9q34.3 and contains three exons and two introns, approximately 14.8 Kb in length. Its cDNA encodes a polypeptide containing 152 amino acids. The primary protein structure of mPGES-1 from different species has more than 80% homology. Research shows that the expression of COX-2 and mPGES-1 increases significantly in a variety of cultured cells with the stimulation of inflammatory factor (LPS, IL-1, etc.), which is accompanied by increased synthesis by PGE2. Immunohistochemical experiments also demonstrate that COX-2 and mPGES-1 are located on the microsome membrane, indicating that mPGES-1 is primarily coupled with COX-2 and that it mediates increased PGE2 synthesis in the delayed reaction caused by inflammation factors. However, investigation of enzyme dynamics shows that inductions of COX-2 and mPGES-1 are not completely concordant and, in certain cases, COX-2 can couple with mPGES-2, and at the same time mPGES. -1 can also be coupled with the COX-1. Furthermore, PGH2 generated by COX-2 catalysis can be synthesized to PGE2 or other types of prostaglandins by the action of mPGES-1. Therefore, the regulatory mechanisms of the expression of COX-2 and mPGES-1 overlap and are different.

Currently, there are two types of mPGES-1 inhibitors, AAD-2004 from the Korean pharmaceutical company GNT (Neurotech) and LY-3023703 from Eli Lilly Company. The AAD-2004 indications are not directed at pain, but rather is a potent spin trapping molecule and microsomal prostaglandin E synthase 1 inhibitor that can be used in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. LY-3023703 is used in the treatment of osteoarthritis pain, which entered the clinical phase in June 2016. At present, there are two patent applications on mPGES-1, WO2012087771 and WO2012161965, disclosed by Eli Lilly Company. Patent applications WO2014 / 167444, WO2011 / 048004, CN 101 490000, WO2013 / 118071, WO2013 / 038308 and WO2013 / 072825 also disclose compounds that can act as inhibitors of mPG-ES-1.

Although a number of microsomal prostaglandin E synthetase 1 (mPGES-1) inhibitors have been disclosed so far, new compounds with better efficacy still need to be developed. After continuous efforts, the present invention obtained a series of compounds of general formula (I), and these compounds were found to have excellent effect and function.

WO2014 / 102376 and WO2014 / 102378 disclose azaindole derivatives that act as protein kinase inhibitors. JP 2011 168515 refers to benzoxazole derivatives used as promoting agents for EPO production. WO2009 / 019504 and WO 2007/091106 describe benzoxazole derivatives that can be used in the treatment of muscular dystrophy. EP 2915 804 discloses amine derivatives as TNF alpha inhibitors. FR 1 587 692 addresses indole derivatives for therapeutic applications. WO 00/76969 refers to isoindoline derivatives used in the treatment of Alzheimer's disease as inhibitors of amyloid protein aggregation. WO 2016/090079 also discloses heteroaryl derivatives that act as protein kinase inhibitors. Martvon et al. (XIII Symposium on the Chemistry of Nucleic Acid Components, Czech Republic, 09/03/2005), Racane, L. et al. (Molecules, 2006, 11, pp. 325-333) and EP 1571142 refer to benzothiazole derivatives with anti-tumor or anti-inflammatory activities.

However, none of these documents refer to heteroaryl derivatives as claimed in the present invention, in particular for use as inhibitors of mPGES-1.

Summary of the invention

The present description refers to a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof,

where:

ring P is selected from a five-membered heteroaryl and a five-membered heterocyclyl;

ring Q is selected from aryl and heteroaryl, preferably phenyl, pyridyl or pyrimidinyl; A, B, or Y is selected from -CH and N;

R1 is selected from alkyl and cycloalkyl, wherein said alkyl or cycloalkyl is further optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, and haloalkyl; R2 is selected from halogen and haloalkyl;

R3 are identical or different, and each is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, oxo, -C (O) OR5 -OC (O) R5, -NHS (O) mR5 , -C (O) R5, -NHC (O) R5, -NHC (O) OR5, -Nr 6R7, -OC (O) NR6R7 or -C (O) NR6R7, wherein said alkyl, cycloalkyl and heterocyclyl are further each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR5 -OC (O ) R5, -NHS (O) mR5, -C (O) R5, -NHC (O) R5, -NHC (O) OR5, -NR6R7, -OC (O) NR6R7 and -C (O) NR6R7;

R4 is selected from aryl and heteroaryl, phenyl is preferred, wherein said aryl and heteroaryl are each further optionally substituted by one or more groups selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR5, -OC (O) R5, -NHS (O) mR5, -C (O) R5, -NHC (O) R5, -NHC (O) OR5, -NR6R7, -OC (O) NR6R7 and -C (O) NR6R7, wherein said haloalkyl is preferably trifluoromethyl;

R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, aryl, and heteroaryl are each further optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and a carboxylate group;

each of R6 and R7 is independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and a carboxylate group; or

R6 and R7 may be taken together with the nitrogen atom to which they are attached to form heterocyclyl, wherein said heterocyclyl may contain one or more heteroatoms selected from the group consisting of N, O, and S (O) m, and wherein said heterocyclyl is further optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and a carboxylate group;

m is 0, 1 or 2;

s is an integer between 0 to 3;

t is 0 or 1.

In an example of the present description, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein when said R2 is halogen, t is 1.

The present invention relates to a compound of general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

ring P is selected from a five-membered heteroaryl and a five-membered heterocyclyl;

ring Q is selected from phenyl and pyridinyl;

A, B or Y is selected from -CH- and N;

R1 is selected from alkyl and cycloalkyl, wherein said alkyl or cycloalkyl is further optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, and haloalkyl; R2 is selected from halogen and haloalkyl;

R3 are identical or different, and each is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, and oxo, wherein said alkyl, cycloalkyl, and heterocyclyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, alkoxy, and alkyl;

R4 is selected from phenyl and pyridinyl, wherein said phenyl and pyridinyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein said haloalkyl is preferably trifluoromethyl;

s is an integer between 0 to 3;

t is 1.

In a preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of formula (II), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH- and N;

the ring P, A, B, Y, s, t and R1 ~ R4 are as defined above in the general formula (I) according to the present invention.

In another example of the present disclosure, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of the formula (III), formula (IV) or formula (V), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH- and N;

E, G, and W are each independently selected from CRa, NRb, N, O, and S;

each of Ra and Rb is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR5, -OC (O) R5, -NHS (O) mR5, -C ( O) R5, - NHC (O) R5, -NHC (O) OR5, -NR6R7, -OC (O) NR6R7 or -C (O) NR6R7, wherein said alkyl, cycloalkyl and heterocyclyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR5, -OC (O) R5, - NHS (O) mR5, -C (O) R5, -NHC (O) R5, -NHC (O) OR5, -NR6R7, -OC (O) NR6R7 and -C (O) NR6R7; Y

A, B, Y, t, R1 ~ R2 and R4 ~ R7 are as defined in the general formula (I).

According to a preferred embodiment of the present invention, the compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of formula (III), formula (IV) or formula (V), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH- and N;

E, G, and W are each independently selected from CRa, NRb, N, O, and S;

each of Ra and Rb is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are each further optionally substituted by one or more groups selected from the group that consists of halogen, hydroxy, alkoxy, and alkyl; Y

A, B, Y, t, R1 ~ R2 and R4 are as defined in general formula (I) according to the present invention.

In another example of the present disclosure, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of the formula (VI), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH- and N;

Rb is selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR5, -OC (O) R5, -NHS (O) mR5, -C (O) R5, -NHC (O) R5, -NHC (O) OR5, -NR6R7, -OC (O) NR6R7 and -C (O) NR6R7, wherein said alkyl, cycloalkyl, and heterocyclyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR5, -OC (O) R5, -NHS (O) mR5, -C (O) R5, -NHC (O) R5, -NHC (O) OR5, -NR6R7, -OC (O) NR6R7 and -C (O) NR6R7; preferably Ci ~ C ⁴ alkyl, C-, ~ C ⁴ alkoxy or tetrahydrofuryl;

A, B, Y, t, R1 ~ R2 and R4 ~ R7 are as defined in the general formula (I).

According to another preferred embodiment of the present invention, the compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of formula (VI), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH and N;

Rb is selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are further each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy and alkyl; Y

A, B, Y, t, R1 ~ R2 and R4 are as defined in general formula (I) according to the present invention.

In another example of the present disclosure, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of the formula (VII), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH- and N;

R ^b is selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) ^m R ⁵ , -C (O ) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ , wherein said alkyl , cycloalkyl, and heterocyclyl are further each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O ) OR ⁵ -OC (O) R ⁵ , -NHS (O) ^m R ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ or -C (O) NR ⁶ R ⁷ ;

R ⁸ is selected from halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) ^m R ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ or -C (O) NR ⁶ R ⁷ , wherein said haloalkyl is preferably trifluoromethyl; Y

A, B, Y, R ¹ ~ R ² and R ⁵ ~ R ⁷ are as defined in the general formula (I).

According to another preferred embodiment of the present invention, the compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of formula (VII), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where:

X is selected from -CH and N;

Rb is selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are further each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy and alkyl;

R8 is selected from halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl, wherein said haloalkyl is preferably trifluoromethyl; Y

A, B, Y, R1 ~ R2 is as defined in general formula (I) according to the present invention.

In another preferred embodiment of the present invention, a compound of formula (VII), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, is a compound of formula (VII-A) or formula (VII-B), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

A, B, X, Y, R1 ~ R2, R8 and Rb are as defined in formula (VII) according to the present invention.

In another preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said A , B and Y are selected from CH.

In another preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein one of A, B and Y is selected from N, the other two are selected from -CH-.

In another embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said groups

include, but are not limited to:

R3 and R4 are as defined in the general formula (I) according to the present invention.

In another example of the present description, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R1 is selects from alkyl and haloalkyl, preferably tertiary butyl, isopropyl,

In another preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R1 is selected from tertiary butyl, isopropyl,

In another preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R1 is selected from cycloalkyl,

wherein said cycloalkyl is further substituted by haloalkyl, R1 is preferably

In another preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R2 it is selected from haloalkyl, preferably -CHF ² .

In another preferred embodiment of the present description a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R2 is selected from haloalkyl and t is 0.

In another preferred embodiment of the present invention, a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R2 it is selected from halogen, preferably chlorine.

In another preferred embodiment of the present invention, a compound of formula (III), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said t is 1

Typical compounds of the present invention include, but are not limited to:

continuation

continuation

continuation

continuation

continuation

continuation

continuation

continuation

continuation

or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a process for preparing the compound of formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, comprising a stage of:

a compound of general formula (IA) or salts thereof are subjected to a condensation reaction with a compound of general formula (IB) under alkaline conditions to give a compound of formula (I);

where:

Rc is selected from hydroxy and halogen;

ring P, ring Q, A, B, Y, s, t and R1 ~ R4 are as defined in general formula (I).

Alkaline reagents include organic base and inorganic base, wherein said organic base includes, but is not limited to, triethylamine, N, N-diisopropylethylamine, pyridine, sodium bis (trimethylsilyl) amide, n-butyllithium, ferc-butanolate potassium or tetrabutylammonium bromide, wherein said inorganic base includes, but is not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate, preferably triethylamine .

Catalysts include, but are not limited to, Pd / C, Raney nickel.

Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbondiimide, 0- (benzotriazol-1-yl tetrafluoroborate ) -N, N, N'N'-tetramethyluronium, 1-hydroxybenzotriazole, l-hydroxy-7-azobenzotriazole, O- (benzotriazol-l-yl) hexafluorophosphate -NNNN-tetramethyluronium, 2- (7-azo- hexafluorophosphate benzotriazol-1-yl) -N, N, N, N, -tetramethyluronium, benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexaflurophosphate or benzotriazol-1-yl-oxy-tripyrrolidinyl-phosphonium hexafluorophosphate. In another example, the present description refers to a compound of formula (IA), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof,

comprising the following groups:

where:

R3 is selected from hydrogen, alkyl, and heterocyclyl, wherein said alkyl is further optionally substituted by one or more groups selected from the group consisting of alkoxy and heterocyclyl, preferably C ¹ ~ C ⁴ alkyl, Ci ~ C ⁴ alkoxy, or tetrahydrofuranyl ;

R4 is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is further optionally substituted by one or more groups selected from the group consisting of halogen and haloalkyl, wherein said haloalkyl is preferably trifluoromethyl; R4 is preferably phenyl, wherein said phenyl is further substituted by a halogen or a haloalkyl. t is 1;

as long as:

when the general formula (IA) is the following groups:

R3 is selected from hydrogen and alkyl, wherein said alkyl is further optionally substituted by one or more groups selected from the group consisting of alkoxy and heterocyclyl;

R4 is phenyl, wherein said phenyl is further substituted by a haloalkyl, wherein said haloalkyl is preferably trifluoromethyl; or

R3 is heterocyclyl;

R4 is phenyl, wherein said phenyl is further substituted by a halogen or a haloalkyl.

In another aspect, the present invention provides a compound of formula (IA), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof,

comprising the following groups:

where:

R3 is selected from hydrogen, alkyl, and heterocyclyl, wherein said alkyl, furthermore, is optionally substituted by one or more alkoxy;

R4 is selected from phenyl and pyridinyl, wherein said phenyl or pyridinyl is substituted with one or more groups selected from the group consisting of halogen and haloalkyl,

wherein said haloalkyl is preferably trifluoromethyl; R4 is preferably phenyl, wherein said phenyl is further substituted by a halogen or haloalkyl;

as long as:

when the general formula (IA) is the following groups:

R3 is selected from hydrogen and alkyl, wherein said alkyl is further optionally substituted by one or more groups selected from alkoxy and heterocyclyl;

R4 is phenyl, wherein said phenyl is further substituted by a haloalkyl, wherein said haloalkyl is preferably trifluoromethyl; or

R3 is heterocyclyl;

R4 is phenyl, wherein said phenyl is further substituted by a halogen or haloalkyl.

Compounds of general formula (IA) include, but are not limited to:

continuation

continuation

continuation

continuation

continuation

or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof.

In another example, the present description refers to a compound of formula (IB), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where,

Rc is selected from hydroxy and halogen; Y

ring Q, R1 and R2 are as defined in general formula (I).

Compounds of general formula (IB) include, but are not limited to:

continuation

or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof.

Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof. themselves, or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers, diluents or excipients. Another aspect of the present description is directed to the use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising to the same, in the preparation of a medicament for the treatment of diseases mediated by microsomal prostaglandin E synthase 1 (mPGES-1).

Another aspect of the present description is directed to the use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising at the same, in the preparation of a medicine for inhibition of microsomal prostaglandin E synthase 1 (mPGES-1).

Another aspect of the present description is directed to the use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising thereto, in the preparation of a medicament for the treatment or prevention of diseases or disorders, wherein said diseases or disorders are selected from the group consisting of inflammation, pain, cancer, diabetes, and diabetic complications or neurodegenerative disorders, and the like, wherein said inflammation includes inflammation associated with autoimmune disease, dermatopathy, lung disease, visceral disease, ear, nose, mouth and throat disease, or cardiovascular disease and the like; wherein the autoimmune disease includes arthritis, osteoarthritis, juvenile rheumatoid arthritis, rheumatoid arthritis, ankylosing spondyloarthritis, gout, rheumatic fever, bursitis, systemic lupus erythematosus (SLE) or multiple sclerosis, and the like; said dermatopathy includes dermatitis, eczema, psoriasis, burns or tissue trauma and the like; said lung disease includes asthma, chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis, and the like; said visceral disease includes inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel disease (IBS), peptic ulcers, cystitis, prostatitis, pancreatitis or nephritis and the like; said ear, nose, mouth and throat disease includes influenza, virus infection, bacterial infection, fever, rhinitis, pharyngitis, tonsillitis, conjunctivitis, iritis, scleritis or uveitis, and the like; said cardiovascular disease includes atherosclerosis, thrombosis, stroke or coronary heart disease, and the like; Such pain includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgery pain, postoperative pain, labor second stage pain, labor pain, chronic pain, persistent pain, pain of peripheral origin, pain of central origin, chronic headache, migraine, sinus headaches, tension headaches, phantom limb pain, neuronal injury or a combination thereof, and the like; such cancer includes prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma, leukemia, lymphoma skin T lymphocyte or skin B lymphocyte lymphoma, and the like; said diabetes and complications of diabetes include diabetic vasculopathy, diabetic neuropathy or diabetic retinopathy, and the like; said neurodegenerative disorder includes Alzheimer's disease or Parkinson's disease; wherein said diseases or disorders are preferably selected from inflammation and pain, more preferably selected from osteoarthritis, rheumatoid arthritis, bursitis, ankylosing spondyloarthritis, or the pain associated with any one of the diseases or disorders listed above.

Another aspect of the present invention is directed to a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising al same, for use as a drug for the treatment of diseases mediated by microsomal prostaglandin E synthase 1 (mPGES-1).

Another aspect of the present invention is directed to a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising al same, for use as a drug for the inhibition of microsomal prostaglandin E synthase 1 (mPGES-1). Another aspect of the present invention is directed to a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising al itself, for use as a drug for the treatment or prevention of diseases or disorders, wherein said diseases or disorders are selected from the group consisting of inflammation, pain, cancer, diabetes, and diabetic complications or neurodegenerative disorders, and the like, in wherein said inflammation includes inflammation associated with autoimmune disease, dermatopathy, lung disease, visceral disease, ear, nose, mouth and throat disease, or cardiovascular disease and the like; wherein the autoimmune disease includes arthritis, osteoarthritis, juvenile rheumatoid arthritis, rheumatoid arthritis, ankylosing spondyloarthritis, gout, rheumatic fever, bursitis, systemic lupus erythematosus (SLE) or multiple sclerosis, and the like; said dermatopathy includes dermatitis, eczema, psoriasis, burns or tissue trauma and the like; said lung disease includes asthma, chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis, and the like; said visceral disease includes inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel disease (IBS), peptic ulcers, cystitis, prostatitis, pancreatitis or nephritis and the like; said ear, nose, mouth and throat disease includes influenza, virus infection, bacterial infection, fever, rhinitis, pharyngitis, tonsillitis, conjunctivitis, iritis, scleritis or uveitis, and the like; said cardiovascular disease includes atherosclerosis, thrombosis, stroke or coronary heart disease, and the like; Such pain includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgery pain, postoperative pain, labor second stage pain, labor pain, chronic pain, persistent pain, pain of peripheral origin, pain of central origin, chronic headache, migraine, sinus headaches, tension headaches, phantom limb pain, neuronal injury or a combination thereof, and the like; such cancer includes prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma, leukemia, lymphoma skin T lymphocyte or skin B lymphocyte lymphoma, and the like; said diabetes and complications of diabetes include diabetic vasculopathy, diabetic neuropathy or diabetic retinopathy, and the like; said neurodegenerative disorder includes Alzheimer's disease or Parkinson's disease; wherein said diseases or disorders are preferably selected from inflammation and pain, more preferably selected from osteoarthritis, rheumatoid arthritis, bursitis, ankylosing spondyloarthritis, or pain associated with any one of the diseases or disorders listed above.

Detailed description of the invention

Unless otherwise indicated, terms used herein have the following meanings.

"Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group that includes 1 to 20 carbon atoms, preferably C-nC ™ alkyl, more preferably C-i ~ C6 alkyl. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl , 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 , 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5 -dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n -nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and the branched isomers thereof. More preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n -pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2 -trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like .

"Alkenyl" refers to an alkyl defined as above having at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like, preferably alkenyl C ^{2 to 10,} more preferably alkenyl C ^{2 to 6,} most preferably alkenyl C ^2-4.

"Alkynyl" refers to an alkyl defined as above having at least two carbon atoms and at least one carbon-carbon triple bond, eg, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like, preferably alkynyl C ^2-10, more preferably C alkynyl ^{2 to 6,} most preferably C alkynyl ^{2 to 4.}

"Cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl and cyclohexenyl. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, a fused ring, or a bridged ring.

"Spirocycloalkyl" refers to a 5 to 20 membered polycyclic group with rings connected through a common carbon atom (called a spiro atom), where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system, preferably 6 to 14 membered spirocycloalkyl, and more preferably 7 to 10 membered spirocycloalkyl. According to the number of common spiro atoms, the spiro cycloalkyl can be divided into mono-spiro cycloalkyl, di spiro cycloalkyl or poly-spiro cycloalkyl and preferably, a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4 members / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyl. Non-limiting examples of spiro cycloalkyls include, but are not limited to:

"Fused cycloalkyl" refers to a 5 to 20 membered, all carbon polycyclic group, where each ring in the system shares an adjacent pair of carbon atoms with another ring, where one or more rings may contain one or more doubles. bonds, but neither ring has a fully conjugated pi electron system, preferably 6 to 14 membered fused cycloalkyl, more preferably 7 to 10 membered fused cycloalkyl. According to the number of ring members, the fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic fused cycloalkyl, and more preferably fused cycloalkyl 5-member / 5-member or 5-member / 6-member bicyclic. Non-limiting examples of fused cycloalkyl include, but are not limited to:

Y

"Bridged cycloalkyl" refers to a 5 to 20 membered, all carbon polycyclic group, where every two rings in the system share two disconnected rings, where the rings may have one or more double bonds, but neither ring has a fully conjugated pi electron system, preferably 6 to 14 membered bridged cycloalkyl and more preferably 7 to 10 membered bridged cycloalkyl. According to the number of ring members, the bridged cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyls include, but are not limited to:

Said cycloalkyl can be fused to aryl, heteroaryl or heterocyclyl, where the ring attached to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

"Heterocyclyl" refers to a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, O, and S (O) ^m (where m is an integer selected from 0 to 2) as ring atoms, but excluding -OO-, -O S- or -SS- in the ring, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl has 3 to 12 atoms with 1 to 4 heteroatoms, more preferably 3 to 10 atoms, and most preferably 5 to 6 atoms. Non-limiting examples of monocyclic heterocyclyl include, but are not limited to, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl, and the like. Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, a fused ring, or a bridged ring.

"Spiro heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclyl with rings connected through a common carbon atom (called a spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of N, O and S (O) ^m (where m is an integer selected from 0 to 2) as ring atoms and the remaining ring atoms are carbon atoms, where one or more rings may contain one or more double bonds, but neither ring has a fully conjugated pi electron system; preferably 6 to 14 membered spiroheterocyclyl, and more preferably 7 to 10 membered spiroheterocyclyl. According to the number of common spiro atoms, spiro heterocyclyl can be divided into mono-spiro heterocyclyl, di-spiro heterocyclyl or poly-spiro heterocyclyl, preferably monospiro heterocyclyl or di-spiro heterocyclyl, and more preferably 4-membered mono-spiro heterocyclyl / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members. Non-limiting examples of spiro heterocyclyls include, but are not limited to:

"Fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of N, O, and S (O) m (where m is an integer selected from 0 to 2) as ring atoms, and the remaining ring atoms are carbon atoms; preferably 6 to 14 membered fused heterocyclyl, and more preferably 7 to 10 membered fused heterocyclyl. According to the number of member rings, the fused heterocyclyl can be divided into fused bicyclic, tricyclic, tetracyclic or polycyclic heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered / 5-membered bicyclic fused heterocyclyl, or 5-membered members / 6 members. Non-limiting examples of fused heterocyclyl include, but are not limited to:

Rings in the system share two disconnected rings, wherein the rings may have one or more double bonds, but neither ring has a fully conjugated pi electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O and S (O) m (where m is an integer selected from 0 to 2) as ring atoms, and the remaining ring atoms are carbon atoms; preferably 6 to 14 membered bridged heterocyclyl, and more preferably 7 to 10 membered bridged heterocyclyl. According to the number of member rings, the bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyls include, but are not limited to:

Said heterocyclyl can be fused to aryl, heteroaryl or cycloalkyl, wherein the ring attached to the parent structure is heterocyclyl. Non-limiting examples include, but are not limited to:

etc.

"Aryl" refers to a 6 to 14 membered full carbon monocyclic ring or a polycyclic fused ring (ie, each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group that has a fully conjugated pyelctronic system; preferably 6 to 10 membered aryl, more preferably phenyl and naphthyl, and most preferably phenyl. Aryl can be fused to heteroaryl, heterocyclyl, or cycloalkyl, where the ring bond to the parent structure is aryl. Non-limiting examples include, but are not limited to:

"Heteroaryl" refers to 5 to 14 membered aryl having 1 to 4 heteroatoms selected from the group consisting of O, S, and N as ring atoms and the remaining ring atoms are carbon atoms; preferably 5 to 10 membered heteroaryl, more preferably 5 or 6 membered heteroaryl, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl and the like. Heteroaryl can be fused to aryl, heterocyclyl, or cycloalkyl, where the ring bond to the parent structure is heteroaryl. Non-limiting examples include, but are not limited to:

Y

"Alkoxy" refers to an -O- (alkyl) or -O- (unsubstituted cycloalkyl) group, wherein the alkyl is as defined above. Non-limiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

"Haloalkyl" refers to an alkyl substituted with one or more halogen, where the alkyl is as defined above.

"Hydroxy" refers to an -OH group.

"Hydroxyalkyl" refers to hydroxy substituted alkyl, where alkyl is as defined above.

"Halogen" refers to fluorine, chlorine, bromine, or iodine.

"Amino" refers to a -NH ² group.

"Cyano" refers to a -CN group.

"Nitro" refers to a -NO ² group.

"Benzyl" refers to a -CH ² -phenyl group.

"Oxo" refers to a group = O.

"Carboxyl" refers to a group -C (O) OH.

"Carboxylic ester" refers to a group -C (O) O (alkyl) or (cycloalkyl), where alkyl and cycloalkyl are as defined above.

"Amino protecting group" refers to a group that prevents amino from reacting when other parts of the molecule are subjected to a reaction that can be easily removed. Non-limiting examples include, but are not limited to, formyl, alkylcarbonyl, alkoxycarbonyl, benzoyl, aralkylcarbonyl, aralkoxycarbonyl, trityl, phthalyl group, N, N-dimethylaminomethylenyl, substituted silicyl, and the like. These groups may be optionally substituted with one to three groups independently selected from the group consisting of halogen, alkoxy, or nitro. The amino protecting group is preferably t-butyloxycarbonyl.

"Optional" or "optionally" means that the event or circumstance described below may occur, but need not occur, and such description includes the situation in which the event or circumstance may or may not occur. For example, "the heterocyclic group optionally substituted with an alkyl" means that an alkyl group may be present, but need not be, and such description includes the situation of the heterocyclic group substituted with an alkyl and the heterocyclic group not substituted with an alkyl.

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that substituents only exist in their possible chemical position. The person skilled in the art can determine whether substitution is possible or impossible by experiment or theory without undue effort. For example, the combination of amino or hydroxy having free hydrogen with carbon atoms having unsaturated (such as olefinic) bonds can be unstable.

A "pharmaceutical composition" refers to a mixture of one or more of the compounds according to the present invention or physiologically / pharmaceutically acceptable salts and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism, which favors the absorption of the active ingredient and, therefore, shows biological activity.

m and R5 to R7 are as defined in the compound of formula (I).

SYNTHESIS METHOD OF THE PRESENT INVENTION

To achieve the object of the present invention, the present invention applies the following technical synthesis solutions.

Scheme 1

A process for preparing a compound of formula (I) of the present invention, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, comprising the following steps :

a compound of formula (la) is subjected to reduction reaction in the presence of catalyst to give a compound of formula (IA) or salts thereof; a compound of formula (IA) or its salts is subjected to a condensation reaction with a compound of formula (IB) under alkaline conditions to give a compound of formula (I); where:

Rc is selected from hydroxy and halogen;

ring P, ring Q, A, B, Y, s, t and R1 to R4 are as defined in the general formula (I).

Scheme 2

A process for preparing a compound of formula (III), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, comprising the following steps:

a compound of formula (IIIa) is subjected to a coupling reaction with a compound of formula (IIIb) in the presence of a catalyst to give a compound of formula (IIIc); a compound of formula (Mie) is subjected to a reduction reaction in the presence of catalyst to give a compound of formula (IIIA) or salts thereof; a compound of formula (IIIA) or its salts is subjected to a condensation reaction with a compound of formula (IIIB) under alkaline conditions to give a compound of formula (III); Where:

Rc is selected from hydroxy and halogen;

Rd is selected from halogen, preferably bromine and iodine;

E, G, and W are each independently selected from CRa, NRb, N, O, and S;

A, B, X, Y, t, R1, R2 and R4 are as defined in formula (I).

A process for preparing a compound of formula (IV) and formula (V) is the same or similar to that of the compound of formula (III).

Scheme 3

A process for preparing a compound of formula (VI), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, comprising the following steps:

a compound of formula (Via) is subjected to a coupling reaction with a compound of formula (IIIb) in the presence of a catalyst to give a compound of formula (VIb); a compound of formula (VIb) is subjected to a reduction reaction in the presence of catalyst to give a compound of formula (VIA) or salts thereof; a compound of formula (VIA) or its salts is subjected to a condensation reaction with a compound of formula (VIB) under alkaline conditions to give a compound of formula (VI);

Rc is selected from hydroxy and halogen;

Rd is selected from halogen, preferably bromine and iodine;

A, B, X, Y, t, R1, R2 and R4 are as defined in formula (I);

Rb is as defined in formula (IV).

Scheme 4

a compound or formula a is subjected to a coupling reaction with a compound or formula (VIb) in the presence of a catalyst to give a compound of formula (Vb); a compound of formula (Vb) is subjected to reduction reaction in the presence of catalyst to give a compound of formula (VA) or salts thereof; a compound of formula (VA) or its salts is subjected to a condensation reaction with a compound of formula (VB) under alkaline conditions to give a compound of formula (VII);

Rc is selected from hydroxy and halogen;

Rd is selected from halogen, preferably bromine and iodine;

A, B, X, Y, R1 and R2 are as defined in formula (I);

Rb is as defined in formula (IV);

R8 is as defined in formula (VII).

Alkaline reagents include organic and inorganic base, wherein said organic base includes, but is not limited to, triethylamine, N, N-disopropylethylamine, pyridine, sodium bis (trimethylsilyl) amide, n-butyllithium, potassium tert-butanolate, or tetrabutylammonium bromide, wherein said inorganic base includes, but is not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate, preferably triethylamine.

Catalysts include, but are not limited to, Pd / C, raney nickel, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium diacetate, (1,1'-bis (dibenzylphosphino) ferrocene) dichloropalladium (II), tris ( dibenzylideneacetone) dipalladium.

Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbondiimide, 0-benzotriazol-1-yl) -N tetrafluoroborate. , N, N ', N-tetramethyluronium, 1-hydroxybenzotriazole, l-hydroxy-7-azobenzotriazole, 0-benzotriazole-hexafluorophosphate, N, N', N-tetramethyluronium, 2- (7-azobenzotriazole-1- hexafluorophosphate yl) -N, N, N'N-tetramethyluronium, benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate.

The present invention will be described in more detail with the following examples, but the examples are not to be construed as limiting the scope of the invention.

Conditions not specified in the examples will be conditions common in the art or conditions recommended for raw materials by the product manufacturer. Reagents whose origin is not indicated will be conventional commercially available reagents.

Examples

Composite structures are identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR is determined by Bruker AVANCE-400. The solvents are deuterated dimethyl sulfoxide (DMSO-cfe), deuterated chloroform (CDCh) and deuterated methanol (CD ³ OD) with tetramethylsilane (TMS) as internal standard. The NMR chemical shifts (8) are given in 10.6 (ppm).

MS is determined using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, type: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 chromatographic column, 150 x 4.6 mm) and a Waters 2695-2996 high pressure liquid chromatography spectrometer (column Gimini C18 chromatography, 150 x 4.6 mm).

Average kinase inhibition rate and IC ⁵⁰ values are determined by a NovoStar ELISA (BMG Co., Germany).

Yantai Huanghai HSGF254 or Qingdao GF254 Silica Gel Plate is used for thin layer silica gel (TLC) chromatography. The dimension of the silica gel plate used in TLC is 0.15mm to 0.2mm, and the dimension of the silica gel plate used in product purification is 0.4mm to 0.5 mm.

Yantai Huanghai silica gel of 200 to 300 mesh is used as a vehicle for column chromatography. The known raw materials of the present invention can be prepared by synthesis methods conventional in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc., or Dari chemical Company, etc.

Unless otherwise indicated, the reactions are carried out under a nitrogen atmosphere or an argon atmosphere.

The term "nitrogen atmosphere" or "argon atmosphere" means that a reaction flask is equipped with a 1 L nitrogen or argon balloon.

The term "hydrogen atmosphere" means that a reaction flask is equipped with a 1 L hydrogen balloon.

Pressurized hydrogenation reactions are performed with a Parr 3916EKX hydrogenation instrument and a QL-500 hydrogen generator or an HC2-SS hydrogenation instrument.

In hydrogenation reactions, the reaction system is generally vacuum and charged with hydrogen, repeating the above operation three times.

The CEM Discover-S 908860 microwave reactor is used in microwave reaction.

Unless otherwise indicated, the solution used in the reactions refers to an aqueous solution. Unless otherwise indicated, the reaction temperature in the reactions refers to room temperature and the temperature range is 20 ° C to 30 ° C.

The reaction process is controlled by thin layer chromatography (TLC), the elution system includes: A: dichloromethane and methanol, B: n-hexane and ethyl acetate, C: petroleum ether and ethyl acetate, D: acetone . The solvent volume ratio can be adjusted according to the polarity of the compounds.

The elution system for the purification of compounds by column chromatography and thin-layer chromatography includes: A: dichloromethane and methanol, B: n-hexane and ethyl acetate, C: n-hexane and acetone, D: n-hexane , E: ethyl acetate. The volume ratio of the solvent can be adjusted according to the polarity of the compounds, and sometimes a little alkaline reagent, such as triethylamine or an acid reagent, can also be added.

Example 1

2- (difluoromethyl) -A / - (1-ethyl-2- (4- (trifluoromethyl) phenyl) -7H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide

Stage 1

Ethyl 5-cyano-2- (difluoromethyl) nicotinate

3-Dimethylaminoacrylonitrile 1a (865 mg, 9.0 mmol, prepared according to the method disclosed in " Pharma Chemica, 2010, 2 (3), 178-186 ") in 20 ml of A /, W-dimethylformamide, and heated to 65 ° C. 5 ml of a solution of 2- (ethoxymethylene) were added dropwise Ethyl -4,4-difluoro-3-oxo-butanoate 1b (2.0 g, 9.0 mmol, prepared according to the method disclosed in the patent application "WO2012025469") in W, A / -dimethylformamide in the solution and stirred for 1 hour. Then, the reaction solution was added with ammonium acetate (1.1 g, 14.0 mmol) and stirred for another 16 hours. The reaction solution was concentrated under reduced pressure, and The residues were added with 100 ml of water and extracted with ethyl acetate (100 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified at via thin layer chromatography (TLC) with a C elution system to obtain the title compound, ethyl 5-cyano-2- (difluoromethyl) nicotinate 1c (606 mg, 30%) as an a light yellow oil.

MS m / z (ESI): 227.1 [M + 1]

Stage 2

Ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinate hydrochloride

Ethyl 5-cyano-2- (difluoromethyl) nicotinate 1c (606 mg, 2.7 mmol) was dissolved in 15 ml of ethanol, and added with concentrated hydrochloric acid (1.0 ml, 37%) and Pd / C (180mg, 10%). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction solution was filtered through celatom, and the filtrate was concentrated under reduced pressure to obtain the title compound, ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinate hydrochloride 1d (709mg, 99%) in the form of a yellow solid.

MS m / z (ESI): 231.1 [M + 1]

Stage 3

Ethyl 2- (Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinate

Ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinate hydrochloride 1d (709 mg, 2.7 mmol) was dissolved in 50 ml of dichloromethane and added with W, W-diisopropylethylamine (1.9 ml, 10, 6 mmol). After the addition was complete, the reaction mixture was added dropwise with a solution of isobutyryl chloride in dichloromethane (0.7M, 5 ml) and then stirred for 2 hours. The reaction mixture was washed with water (50 ml) and a saturated sodium bicarbonate solution (50 ml) successively. The organic phase was concentrated under reduced pressure to obtain the title compound, ethyl 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinate 1e (790 mg, 99%) as a yellow solid Sure.

MS m / z (ESI): 301.1 [M + 1]

Stage 4

2- (Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid

Ethyl 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinate 1e (790 mg, 2.6 mmol) was dissolved in 10 ml of 1,4-dioxane and added with 5 ml of water and hydrate of lithium hydroxide (291 mg, 6.9 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residues were added with 5 ml of water and adjusted to pH2 by 5M hydrochloric acid. Much solid was precipitated and filtered. The filtrate was extracted with ethyl acetate (50 mlx3). The organic phases were combined and concentrated under reduced pressure. The residues were combined with the above filter cake, washed with water and dried to obtain the title compound, 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid 1f (420 mg, 56% ) as a light yellow solid. MS m / z (ESI): 273.1 [M + 1]

Stage 5

2- (Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinoyl acid 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic chloride 1f (150 mg, 0.55 mmol) was dissolved in 5 ml of dichloromethane, and was added with one drop of W, W-dimethylformamide and thionyl chloride (197 mg, 1.65 mmol). After the addition was complete, the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound, 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinoyl chloride 1 g (160 mg) as a light yellow oil. , which was used in the next step without further purification.

Stage 6

1-Ethyl-5-nitro-2- (4- (trifluoromethyl) phenyl) - '/ H-indole

1-Ethyl-5-nitro-tH-indole 1h (500 mg, 2.63 mmol, prepared according to the method disclosed in "Bioorganic & Medicinal Chemistry, 2005, 13 (10), 3531-3541") was dissolved in 5 ml of A /, W-dimethylacetamide, and added with 4-iodotrifluorotoluenoli (790 mg, 2.92 mmol), triphenylphosphine (140 mg, 0.53 mmol), palladium acetate (30 mg, 0.13 mmol) and cesium acetate (1.6 g, 5.21 mmol) successively. After the addition was complete, the resulting mixture was heated to 140 ° C and stirred for 18 hours under an atmosphere of argon. The reaction mixture was concentrated under pressure reduced. The residues were added with 50 ml of ethyl acetate, washed with water (20 mlx2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, the residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 1-ethyl-5-nitro-2- (4- (trifluoromethyl) phenyl ) -7H-indole 1j (130 mg, 14.8%) as a yellow solid.

MS m / z (ESI): 335.1 [M + 1]

Stage 7

1- Ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole

1-Ethyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole 1j (130 mg, 0.39 mmol) was dissolved in 10 ml of tetrahydrofuran and methanol mixture (V: V = 1: 1) and was added with Raney nickel (30 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 1k ( 120 mg) as a light yellow solid, which was used in the next step without further purification.

MS m / z (ESI): 305.1 [M + 1]

Stage 8

2- (Difluoromethyl) -W- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -7H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide 1-ethyl- -5-amino-2- (4- (trifluoromethyl) phenyl) -7H-indole 1k (120 mg, 0.39 mmol) in 10 ml of tetrahydrofuran, and added dropwise with triethylamine (0.10 ml, 0 , 78 mmol) and 5 ml of solution of 2-(difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinoyl chloride 1 g (160 mg, 0.55 mmol) in tetrahydrofuran. The reaction mixture was stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residues were purified via thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -A / - (1-ethyl-2- (4- (trifluoromethyl) phenyl ) -7H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide 1 (25mg, 11.5%) as a yellow solid.

MS m / z (ESI): 559.3 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.61 (s, 1H), 8.68 (s, 1H), 8.46 (t, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.93-7.86 (d, 2H), 7.85-7.78 (d, 2H), 7.61-7.55 (d, 1H), 7.47-7 , 42 (d, 1H), 7.19 (t, 1H), 6.70 (s, 1H), 4.47-4.39 (d, 2H), 4.31-4.20 (m, 2H ), 2.49-2.41 (m, 1H), 1.21 (t, 3H), 1.09-1.03 (d, 6H).

Example 2

2-Chloro-N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -7H-indol-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide

Stage 1

2-Dloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl acid 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoic chloride 2a (500 mg, 1.86 mmol, prepared according to the method disclosed in the patent application "WO2012025469") in 10 ml of dichloromethane, and was added dropwise with thionyl chloride (0.4 ml, 5.58 mmol) and a drop of A /, W -dimethylformamide. After the addition is complete, the reaction mixture is stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound 2-doro-5 - ((2,2-dimethylpropanoylamino) -methyl) benzoyl chloride 2b (550 mg) as a yellow oil, the which was used in the next step without further purification.

Stage 2

2-Chloro-W- (1-ethyl-2- (4- (trifluoromethyl) phenyl) - '/ H-indol-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide

1-Ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) - '/ H-indole-1k (90 mg, 0.27 mmol) was dissolved in 5 ml of tetrahydrofuran, and added dropwise with triethylamine (75 µl, 0.54 mmol) and 2 ml solution of 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (77 mg, 0.27 mmol) in tetrahydrofuran. After the addition was complete, the reaction mixture was stirred for 1 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-W- (1-ethyl-2- (4- (trifluoromethyl) phenyl) - '/ H -indol-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide 2 (45 mg, 30%) as a light yellow solid.

MS m / z (ESI): 557.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.40 (s, 1H), 8.18 (t, 1H), 8.10 (s, 1H), 7.92-7.87 (d, 2H ), 7.84-7.79 (d, 2H), 7.58 7.53 (d, 1H), 7.52-7.48 (d, 1H), 7.47-7.41 (m, 2H), 7.36-7.30 (d, 1H), 6.69 (s, 1H), 4.34-4.29 (d, 2H), 4.29-4.21 (m, 2H) , 1.21 (t, 3H), 1.13 (s, 9H).

Example 3

2-chloro-M- (2- (4-fluorophenyl) -1H-p¡rrolo (2.3-d) p¡r¡d¡n-5-¡l) -5 - ((22-dimethylpropane Lam¡no) met¡l) -benzam¡da

Stage 1

3 - ((4-Fluorophenyl) ethynyl) -5-nitro-pyridin-2-amine

2-amino-3-bromo-5-nitro-pyridine 3b (1.0 g, 4.6 mmol), 1-ethynyl-4-fluoro-benzene 3a (1.24 g, 10.3 mmol) were added, Bis (triphenylphosphine) palladium (II) chloride (0.25 g, 0.35 mmol), copper iodide (7 mg, 0.35 mmol) and triethylamine (0.7 ml, 4.6 mmol) in 20 ml W, A / -dimethylformamide. The reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was filtered with celatom and the filtrate was concentrated under reduced pressure. The residues were purified by column chromatography on silica gel with elution system C to obtain the crude title compound, 3 - ((4-fluorophenyl) ethynyl) -5-nitro-pyridin-2-amine 3c (1 , 7 g) as a brown solid, which was used in the next step without further purification.

MS m / z (ESI): 256.0 [M-1]

Stage 2

2- (4-Fluorophenyl) -5-nitro-1H-pyrrolo [2,3-d] pyridine

3 - ((4-fluorophenyl) ethynyl) -5-nitro-pyridin-2-amine 3c (1.7 g, 4.6 mmol) and potassium tert-butoxide (1.0 g, 9.2 mmol) were dissolved in 20 ml of N, N-dimethylformamide. The reaction mixture was heated to 70 ° C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. The residues were added with 200 ml of water and then filtered with celatom. The filter cake was purified by column chromatography on silica gel with elution system C, and then added with 20 ml of dichloromethane and then filtered. The residues were dried to obtain the crude title compound, 2- (4-fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pindine 3 d (564 mg) as a yellow solid. which was used in the next step without further purification.

Stage 3

2- (4-Fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pindine

2- (4-fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pindin 3d (64 mg, 0.25 mmol) was dissolved in 10 ml of tetrahydrofuran-methanol mixture (V: V = 1 : 1), and then added with Raney nickel (30 mg). The reaction mixture was stirred for 1 hour under an atmosphere of hydrogen and then filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pindine 3e (60 mg) as an oil of brown color, which was used in the next step without further purification.

MS m / z (ESI): 226.1 [M-1]

Stage 4

2-Chloro-N- (2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pindin-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide

2- (4-fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pindine 3e (60 mg, 0.25 mmol) was dissolved in 8 ml of tetrahydrofuran, and added dropwise with triethylamine ( 0.43 ml, 0.31 mmol) and 5 ml of 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl chloride solution 2b (220 mg, 0.76 mmol) in tetrahydrofuran. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-N- (2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] Pyridin-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide 3 (5 mg, 4.2% over two steps) as a light yellow solid.

MS m / z (ESI): 479.4 [M + 1]

1H NMR (400 MHz, DMSO-de): 89.16 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.65-7.56 (m, 1H) , 7.55-7.46 (m, 2H), 7.48 7.36 (m, 2H), 7.27-7.16 (m, 3H), 6.41 (s, 1H), 5, 15 (m, 1H), 4.26-4.21 (m, 2H), 1.13 (s, 9H).

Example 4

2-Chloro-N- (1-eth¡l-2- (4-fluorophenyl) -1H-p¡rrolo [2.3-b1p¡r¡d¡n-5-¡l) 5 - ((2.2- d¡met¡lpropane¡lam¡no) methyl) -benzam¡da

Stage 1

1-Ethyl-2- (4-fluorophenyl) -5-nitro-1H-p¡rrolo [2,3- £)] p¡r¡d¡na

2- (4-Fluorophenyl) -5-nitro-1H-p¡rrolo [2.3- £)] p¡r¡d¡na 3 d (60 mg, 0.23 mmol) were added, iodoethane (40 µl, 0.47 mmol) and cesium carbonate (150 mg, 0.47 mmol) in 5 ml of A /, Wd¡methylformamide. The reaction mixture was stirred for 16 hours, and then added with 20 ml of water, extracted with ethyl acetate (20 mlx4). The organic phases were combined, washed with a saturated sodium chloride solution (30 mlx2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. at reduced pressure. The residues were purified by silica gel column chromatography with an elution system C to obtain the crude title compound, 1-ethyl-2- (4- fluorophenyl) -5-nitro-1H-p¡rrolo [2,3- £)] p¡r¡d¡na 4a (70 mg) as a yellow solid, the which was used in the next stage without additional purification.

MS m / z (ESI): 286.1 [M + 1]

Stage 2

1- Ethyl-2- (4-fluorophenyl) -5-amino-1H-p¡rrolo [2,3- £)] p¡r¡d¡na

1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-p¡rrolo [2,3- £)] p¡r¡d¡na 4a ( 70 mg, 0.23 mmol) in 10 ml of mixture of tetrahydrofuran and methanol (V: V = 1: 1), and then added with Raney nickel (20 mg). The reaction mixture was stirred for 2 hours in a hydrogen atmosphere and then filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-ethyl-2- (4-fluorophenyl) -5-amine-1H-pyrrolo [ 2,3- £)] p¡r¡na 4b (60 mg) in the form of a light yellow solid, which was used in the next stage without pur¡ additional rating. MS m / z (ESI): 256.2 [M + 1]

Stage 3

2- Chloro-W- (1-ethyl-2- (4-fluorophenyl) -1H-p¡rrolo [2,3-8] p¡r¡d¡n-5-¡l) -5 - ((2,2-d¡met¡lpropano¡lam¡no) methyl) -benzam¡da 1-et¡l-2- (4-fluorophen¡l) -5-am was dissolved ¡No-1H-p¡rrolo [2.3-8] p¡r¡d¡na 4b (60 mg, 0.23 mmol) in 5 ml of tetrahydrofuran, and added dropwise with tr Ethylamine (65 µl, 0.47 mmol) and 5 ml of 2-chloro-5 - ((2,2-di-methylpropanelamine) chloride solution ) benzoyl 2b (220 mg, 0.76 mmol) in tetrahydrofuran. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2-chloro-A / - (1-ethyl -2- (4-fluorophenyl) -1H-p¡rrolo [2,3-8] p¡r¡d¡n-5-¡l) -5 - ((2,2-d¡methylpropane Lamino) methyl) -benzamin 4 (5 mg, 4.2% over three steps) as a yellow solid.

MS m / z (ESI): 507.3 [M + 1]

1H NMR (400 MHz, DMSO-d6): 89.15 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.66-7.56 (m, 1H) , 7.55-7.48 (m, 2H), 7.48 7.38 (m, 2H), 7.27-7.17 (m, 3H), 6.56 (s, 1H), 4, 34-4.28 (d, 2H), 4.29-4.20 (m, 2H), 1.23 (t, 3H), 1.12 (s, 9H).

Example 5

2- (D¡fluorometh¡l) -N- (1-eth¡l-2- (4-fluorophen¡l) -1H-¡ndol-5-¡l) -5 - ((2-methylpropane¡ lam¡no) met¡l) n¡cot¡nam¡da

Stage 1

1-Ethyl-2- (4-fluorophenyl) -5-nitro-1 H-indole 5b 1 -Ethyl-3- (4-fluorophenyl) -5-nitro-1 W-indole 5c

1-Ethyl-5-nitro-1 H-indole 1h (1.64 g, 6.17 mmol) was dissolved in 20 ml of A /, H-dimethylacetamide, and then added with 1-fluoro-4-iodo- benzene 5a (4.65 g, 21.0 mmol), triphenylphosphine (360 mg, 1.36 mmol), palladium acetate (70 mg, 0.31 mmol) and cesium acetate (4.0 g, 12.3 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 1-ethyl-2- (4-fluorophenyl) -5-nitro-1 H-indole 5b (0.51 g, 29.1%) as a yellow solid and 1-ethyl-3- (4-fluorophenyl) -5-nitro-1H-indole 5c (125 mg, 7.1%) as a yellow solid.

5b: MS m / z (ESI): 285.0 [M + 1]

5c: MS m / z (ESI): 285.1 [M + 1]

Stage 2

1- Ethyl-2- (4-fluorophenyl) -5-amino-1 H-indole

1-Ethyl-2- (4-fluorophenyl) -5-nitro-1 H-indole 5b (35 mg, 0.12 mmol) was dissolved in 10 ml of tetrahydrofuran and methanol mixture (V: V = 1: 1) , and then added with Raney nickel (10 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen and then filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d (31 mg) as a yellow solid, which was used in the next step without further purification.

MS m / z (ESI): 255.2 [M + 1]

Stage 3

2- (Difluoromethyl) -M- (1-ethyl-2- (4-fluorophenyl) -1H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide

1-Ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d (31 mg, 0.12 mmol) was dissolved in 5 ml of acetonitrile, and then added dropwise with triethylamine (31 µl, 0.22 mmol) and 5 ml of 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinoyl chloride solution 1 g (32 mg, 0.11 mmol) in acetonitrile. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -H- (1-ethyl-2- (4-fluorophenyl) -1H-indole- 5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamidanicotinamide 5 (35 mg, 62.5%) as a yellow solid.

MS m / z (ESI): 509.3 [M + 1]

1H NMR (400MHz, DMSO-da): 88.70 (s, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.63-7.54 (m, 2H) , 7.46-7.51 (d, 2H), 7.44 7.39 (d, 2H), 7.32-7.25 (m, 2H), 7.12 (t, 1H), 6, 51 (s, 1H), 5.36 (t, 1H), 4.53 (s, 2H), 4.30-4.21 (m, 2H), 1.27 (t, 3H), 1.20 -1.14 (d, 6H).

Example 6

2-Bromo-N- (1-ethyl-3- (4-fluorophenyl) -1Hndol-5-¡l) 5 - ((2,2-d¡methylpropane¡lamno) met¡l) -benzam¡da

Stage 1

2-Bromo-5 - ((2,2-d¡metalpropane¡lam¡no) methyl) benzoyl chloride

2-Bromo-5 - ((2,2-dimethylpropanelamine) methyl) benzoic acid 6a (500 mg, 1.59 mmol, prepared from according to the method swelled in the patent application "US20120157506") in 10 ml of dichloromethane, and then added with thonyl chloride (0.4 ml, 4, 78 mmol) and a drop of A /, Wd¡met¡lformam¡da. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure to obtain the crude title compound, 2-bromo-5 - ((2,2-dimet ¡Lpropano¡lam¡no) -me¡l) benzoyl 6b (530 mg) as a light yellow solid, which was used in the next stage without pur¡f Additional cac¡ón.

MS m / z (ESI): 331.1 [M-1]

Stage 2

1- Ethyl-3- (4-fluorophenyl) -5-amino-1H-andol

1-Ethyl-3- (4-fluorophenyl) -5-nitro-1H-indole 5c (110 mg, 0.39 mmol) was dissolved in 10 ml of tetrahydric mixture drofuran and methanol (V: V = 1: 1), and added with Raney nickel (20 mg). The reaction mixture was stirred for 2 hours in a hydrogen atmosphere and then filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-ethyl-3- (4-fluorophenyl) -5-amine-1H-indole 6c ( 100 mg) in the form of a gray solid, which was used in the next stage without additional purification.

MS m / z (ESI): 255.2 [M + 1]

Stage 3

2- Bromo-W- (1-eth¡l-3- (4-fluorophenyl) -1H-¡ndol-5-¡l) -5 - ((2,2-d¡met¡lpropane¡lam¡ no) met¡l) -benzam¡da

1-Ethyl-3- (4-fluorophenyl) -5-amino-1H-indole 6c (100 mg, 0.39 mmol) was dissolved in 5 ml of tetrahydrofuran, and added dropwise with triethylamine (63 μl, 0 , 45 mmol) and 5 ml of 2-bromo-5 - ((2,2-dimethylpropanolamine) methyl) benzoyl chloride solution 6b (50 mg, 0.15 mmol) in tetrahydrofuran. The reaction was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-bromo-W- (1-ethyl-3- (4-fluorophenyl) -1H-indole-5 -L) -5 - ((2,2-di-methylpropanolamno) methyl) -benzamide 6 (15 mg, 18.2%) as a yellow solid. MS m / z (ESI): 551.3 [M + 1]

1H NMR (400 MHz, DMSO-d6): 88.17 (s, 1H), 7.99 (s, 1H), 7.66-7.56 (m, 4H), 7.55-7.50 ( m, 3H), 7.43-7.37 (m, 1H), 7.25-7.19 (m, 1H), 7.15 (t, 1H), 6.28 (s, 1H), 4 , 46-4.36 (d, 2H), 4.30-4.20 (m, 2H), 1.55 (t, 3H), 1.25 (s, 9H).

Example 7

2-Bromo-N- (1-ethyl-2- (4-fluorofeml) -1H-indol-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide

1-Ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d (30 mg, 0.12 mmol) was dissolved in 5 ml of tetrahydrofuran, and then added dropwise with triethylamine (63 μl, 0.45 mmol) and 5 ml of solution of 2-bromo-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 6b (50 mg, 0.15 mmol) in tetrahydrofuran. The reaction mixture was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-bromo-W- (1-ethyl-2- (4-fluorophenyl) -1H-indole-5- yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide 7 (5 mg, 10.4%) as a yellow solid.

MS m / z (ESI): 551.3 [M + 1]

1H NMR (400 MHz, DMSO-d6): 88.00 (s, 1H), 7.90 (s, 1H), 7.65-7.56 (m, 2H), 7.54-7.48 ( m, 2H), 7.47-7.38 (m, 2H), 7.28-7.17 (m, 3H), 6.52 (s, 1H), 6.22 (s, 1H), 4 , 50-4.40 (d, 2H), 4.25-4.16 (m, 2H), 1.33 (t, 3H), 1.27 (s, 9H).

Example 8

2-Chloro-N- (1-ethyl-2- (4-fluorofeml) -1H-indol-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) -benzamide

1-Ethyl-2- (4-fluoropheml) -5-amino-1H-indole 5d (38 mg, 0.15 mmol), 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) acid were dissolved benzoic 2a (40 mg, 0.15 mmol), 1-ethyl- (3-dimethylamnopropyl) -carbohydrate hydrochloride (57 mg, 0.3 mmol), 1-hydroxybenzotriazole (2 mg, 0.015 mmol) and NN-diisopropylethylamine (38 mg, 0.3 mmol) in 5 ml N, N- dimethylformamide. The reaction mixture was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-N- (1-ethyl-2- (4-fluorophenyl) -1H- Ndol-5-¡l) 5 - ((2,2-d¡metalpropano¡lam¡no) methyl) -benzamide 8 (5 mg, 6.7%) as a yellow solid . MS m / z (ESI): 506.0 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.64 (s, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.95-7.90 (d, 2H ), 7.82-7.77 (d, 2H), 7.57 7.47 (d, 2H), 7.48-7.45 (m, 2H), 7.30-7.22 (m, 1H), 6.72 (s, 1H), 4.40-4.36 (d, 2H), 4.33-4.29 (m, 2H), 1.21 (t, 3H), 1.12 (s, 9H)

Example 9

2- (D¡fluorometh¡l) -N- (1-methyl-2- (4- (tr¡fluorometh¡l) phen¡l) -1H¡ndol-5-¡l) 5 - ((2 -met¡lpropane¡lam¡no) met¡l) -n¡cot¡nam¡da

Stage 1

1-Methyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-andol 9b

1-Methyl-5-nitro-1H-indole 9a (1.0 g, 5.7 mmol) was dissolved in 40 ml of N, N-dimethylacetamide, and added with 4 iodotrifluorobenzene 1i (1.7 g, 6.2 mmol), triphenylphosphine (300 mg, 1.4 mmol), palladium acetate (130 mg, 0.57 mmol) and cesium acetate (2.2 g, 1, 4 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residues were added with 50 ml of ethyl acetate, washed with water (20 mlx2), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residues were purified by column chromatography on silica gel with elution system B to obtain the title compound 1-methyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1 H-indole 9b (350 mg, 19.4%) as a yellow solid.

MS m / z (ESI): 321.1 [M + 1]

Stage 2

1- Methyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole-1-methyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1 H-indole 9b ( 350 mg, 1.1 mmol) in 10 ml of tetrahydrofuran and then added with Raney nickel (35 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-methyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 9c (300 mg) as a brown oil, which was used in the next step without further purification.

MS m / z (ESI): 291.2 [M + 1]

Stage 3

2- (Difluoromethyl) -N- (1-methyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) 5 - ((2-methylpropanoylamino) methyl) -nicotinamide 1-methyl- 5-amino-2- (4- (trifluoromethyl) phenyl) -1 H-indole 9c (150 mg, 0.52 mmol), 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid 1f ( 141 mg, 0.52 mmol), 0-benzotriazol-1-yl) -N, N, N, N, -tetramethyluronium (250 mg, 0.78 mmol) and N, N-diisopropylethylamine (100 mg, 0.78 mmol) in 5 ml of N, N-dimethylformamide. The reaction mixture was heated to 75 ° C and then stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -N- (1-methyl-2- (4- (trifluoromethyl) phenyl) -1Hindole -5-yl) 5 - ((2-methylpropanoylamino) methyl) -nicotinamidanicotinamide 9 (10 mg, 2.0%) as a brown solid.

MS m / z (ESI): 545.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.64 (s, 1H), 8.68 (s, 1H), 8.50-8.47 (m, 1H), 8.09 (s, 1H ), 8.03 (s, 1H), 7.90-7.85 (m, 4H), 7.56-7.54 (m, 1H), 7.48-7.45 (m, 1H), 7.28-7.20 (m, 1H), 6.75 (s, 1H), 4.44-4.42 (d, 2H), 3.80 (s, 3H), 2.47 2.46 (m, 1H), 1.07-1.05 (d, 6H)

Example 10

2- (Difluoromethyl) -N- (1-ethyl-2- (4-chlorophenyl) -1H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide

Stage 1

1-Ethyl-2- (4-chlorophenyl) -5-nitro-1 H-indole

1-Ethyl-5-nitro-1 H-indole 1h (439 mg, 2.3 mmol) was dissolved in 5 ml of A /, W-dimethylacetamide, and added with 1-chloro-4-iodo-benzene 10a ( 500 mg, 2.1 mmol), triphenylphosphine (110 mg, 0.42 mmol), palladium acetate (24 mg, 0.11 mmol) and cesium acetate (806 mg, 4.2 mmol) successively. The reaction mixture was heated to 140 ° C and then stirred for 18 hours under an atmosphere of argon. The reaction mixture was filtered. The filtrate was added with 150 ml of ethyl acetate, and then, it was washed with water (20 ml × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by column chromatography on silica gel with a C elution system to obtain the title compound, 1-ethyl-2- (4-chlorophenyl) -5-nitro-1 H-indole 10b (80 mg, 12.7%) as a yellow solid.

Stage 2

1- Ethyl-2- (4-chlorophenyl) -5-amino-1 H-indole

1-Ethyl-2- (4-chlorophenyl) -5-nitro-1 H-indole 10b (80 mg, 0.27 mmol) was dissolved in 20 ml of tetrahydrofuran and methanol mixture (V: V = 1: 1) , and then added with Raney nickel (10 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen, and then filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-ethyl-2- (4-chlorophenyl) -5-amino-1H-indole 10c (72 mg) as a gray solid, which was used in the next step without further purification.

MS m / z (ESI): 271.1 [M + 1]

Stage 3

2- (Difluoromethyl) -W- (1-ethyl-2- (4-chlorophenyl) -1H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide

1-Ethyl-2- (4-chlorophenyl) -5-amino-1 H-indole 10c (50 mg, 0.18 mmol), 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) acid were dissolved nicotinic If (55 mg, 0.18 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (70 mg, 0.37 mmol) and 1-hydroxyben-zotriazole (25 mg, 0.18 mmol) in 3 ml of A /, W-dimethylformamide successively. The reaction mixture was heated to 40 ° C and then stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -N- (1-ethyl-2 - (4-chlorophenyl) -1H-indol-5-yl) -5 - ((2-methylpropanoylamino) methyl) nicotinamidanicotinamide 10 (20 mg, 27.8%) as a yellow solid. MS m / z (ESI): 525.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.57 (s, 1H), 8.65 (s, 1H), 8.44 (t, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.59 (s, 2H), 7.52 (d, 1H), 7.41 (d, 1H), 7.39 (s, 1H), 6.57 (s, 1H) , 4.42 (d, 2H), 4.21 (d, 2H), 3.89 (s, 1H), 1.25 (d, 3H), 1.22 (t, 2H), 1.03 ( d, 6H).

Example 11

2-Chloro-N- (2- (4-fluorophenyl) -1-methyl-1H-¡ndol-5-¡l) -5 - ((2.2-dimethylpropane¡lam¡no) met¡ l) benzamida

Stage 1

2- (4-Fluorophenyl) -1-methyl-5-nitro-1 H-indole

1-Methyl-5-nitro-1 H-indole 9a (0.8 g, 4.5 mmol) was dissolved in 10 ml of A /, H-dimethylacetamide, and then added with 1-fluoro-4-iodo- benzene 5a (1.12 g, 5.0 mmol), triphenylphosphine (238 mg, 0.9 mmol), palladium acetate (51 mg, 0.23 mmol) and cesium acetate (1.7 g, 0.91 mmol) successively. The reaction mixture was heated to 140 ° C, and then stirred for 18 hours under an atmosphere of argon. The reaction solution was cooled to room temperature and then added with 50 ml of water, extracted with ethyl acetate (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by column chromatography on silica gel with a C elution system to obtain the title compound 2- (4-fluorophenyl) -1-methyl-5-nitro-1H-indole 11a (130 mg, 10 , 7%) as a yellow solid.

MS m / z (ESI): 271.1 [M + 1]

Stage 2

2- (4-Fluorophenyl) -1-methyl-5-amino-1 H-indole

2- (4-fluorophenyl) -1-methyl-5-nitro-1 H-indole 11a (130 mg, 0.48 mmol) was dissolved in 16 ml of tetrahydrofuran and methanol mixture (V: V = 1: 1) , and then added with Raney nickel (15 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen and then filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-fluorophenyl) -1-methyl-5-amino-1H-indole 11b (130 mg) as a yellow solid which it was used in the next step without further purification.

Stage 3

2-Chloro-H- (2- (4-fluorophenyl) -1-methyl-1H-indol-5-yl) 5 - ((2,2-dimethylpropanoylamino) methyl) benzamide

2- (4-fluorophenyl) -1-methyl-5-amino-1H-indole 11b (70 mg 0.29 mmol) was dissolved in 20 ml of tetrahydrofuran, and then added dropwise with triethylamine (85 µl, 0.60 mmol) and 5 ml of 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl chloride solution 2b (83 mg, 0.29 mmol) in tetrahydrofuran. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-H- (2- (4-fluorophenyl) -1 -methyl-1H-indol-5-yl) -5 - ((2,2-dimethylpropanoylamino) methyl) benzamide 11 (40 mg, 28.0%) as a yellow solid.

MS m / z (ESI): 492.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 88.01 (s, 1H), 7.91 (s, 1H), 7.65-7.56 (m, 2H), 7.54-7.49 ( m, 2H), 7.48-7.38 (m, 2H), 7.28-7.17 (m, 3H), 6.52 (s, 1H), 6.22 (s, 1H), 4 , 25-4.16 (m, 2H), 3.83 (t, 3H), 1.27 (s, 9H).

Reference example 12

2- (D¡fluorometh¡l) -N- (1-eth¡l-1H-¡ndol-5-¡l) -5 - ((2-methylpropano¡lam¡no) methyl) n¡ cot¡nam¡da

1-Ethyl-1H-indole-5-amine 12a (50 mg, 0.31 mmol, prepared according to "B¡oorgan¡c & Med¡c¡nal Chem¡stry, 2005, 13 (10), 3531-3541 "), 2- (d¡fluorometh¡l) -5 - ((2-methylpropane¡lam¡no) methyl) n¡cotin¡co If acid (70 mg , 0.26 mmol), O-benzotrazole-1-¡l) -N, N, N ', N'-tetramethyluron-tetrafluoroborate (124 mg, 0.39 mmol) and N, N- d¡¡soprop¡let¡l-amine (100 mg, 0.78 mmol) in 5 ml of N, Nd¡met¡lformam¡da successively. The reaction mixture was heated to 75 ° C and then stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2- (d¡fluorometh¡l) -N- (1-eth¡l-1H-¡ndol-5-¡l) -5 - ((2-methylpropane¡lam¡no) methyl l) Nitrogen 12 (20 mg, 18.9%) as a brown solid.

MS m / z (ESI): 415.1 [(M + 1])

1H NMR (400 MHz, DMSO-da): 610.53 (s, 1H), 8.67 (s, 1H), 8.46 (t, 1H), 7.99 (s, 2H), 7.50 -7.44 (d, 1H), 7.42-7.34 (m, 2H), 7.18 (t, 1H), 6.46-6.40 (d, 1H), 4.47-4 , 39 (d, 2H), 4.25-4.15 (m, 2H), 2.49-2.41 (m, 1H), 1.36 (t, 3H), 1.10-1.01 (d, 6H).

Example 13

N- (2- (4-Chlorophenyl) -1-methyl-1H-andol-5-¡l) -2- (d¡fluorometh¡l) -5- (2-methylpropano¡lam No) met¡l) n¡cot¡nam¡da

Stage 1

2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-indole

1-Methyl-5-nitro-1 H-indole 9a (3.30 g, 18.7 mmol) was dissolved in 20 ml of N, N-dimethylacetamide, and then added with 1-chloro-4-iodo-benzene 10a (4.96 g, 20.8 mmol), triphenylphosphine (982 mg, 3.75 mmol), palladium acetate (210 mg, 0.94 mmol) and cesium acetate (7.20 g, 3.75 mmol ) successively. The reaction mixture was heated to 140 ° C, and then stirred for 18 hours under an atmosphere of argon. The reaction solution was cooled to room temperature and then added with 50 ml of water, extracted with ethyl acetate (50 ml). The organic phase was washed with a saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system C to obtain the title compound, 2- (4-chlorophenyl) -1-methyl-5-nitro- 1H-indole 13a (270 mg, 5.0%) as a yellow solid.

Stage 2

2- (4-Chlorophenyl) -1-methyl-5-amino-1H-indole

2- (4-chlorophenyl) -1-methyl-5-nitro-1H-indole 13a (80 mg, 0.28 mmol) was dissolved in 20 ml of tetrahydrofuran and methanol mixture (V: V = 1: 1), and then added with Raney nickel (8 mg). The reaction mixture was stirred for 1 hour under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-chlorophenyl) -1-methyl-5-amino-1H-indole 13b (72 mg) as an off-white solid, which was used in the next step without further purification.

Stage 3

N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide

2- (4-chlorophenyl) -1-methyl-5-amino-1H-indole 13b (72 mg, 0.28 mmol), 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid were dissolved If (77 mg, 0.28 mmol), 1-ethyl- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) and 1-hydroxybenzotriazole (38 mg, 0.28 mmol) in 5 ml of N, N-dimethylformamide successively. The reaction mixture was heated to 40 ° C and then stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain a solid. The solid was added with 20 ml of dichloromethane, and stirred for 20 min to obtain the title compound, N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- ( Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide 13 (20mg, 14.0%) as a yellow solid.

MS m / z (ESI): 511.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.59 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.04 (d, 2H), 7, 62 (dd, 4H), 7.47 (dd, 2H), 7.20 (t, 1H), 6.64 (s, 1H), 4.43 (d, 2H), 3.76 (s, 3H ), 2.46 (m, 1H), 1.06 (d, 6H).

Example 14

N- (2- (4-Chlorophenyl) -1-methyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2 -metal-propanoyl) amino) methyl) n¡cot¡nam¡da

Stage 1

2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotinato

Ethyl 5- (amnomethyl) -2- (d¡fluorometal) nitrite 1d hydrochloride (2.18 g, 8.20 mmol) was dissolved in 20 ml of N, N- di methylformamide, and then added with 2-fluorosobutyric acid (1.04 g, 9.83 mmol), 1 - (3-d¡meth¡lam¡noprop¡l) -3-eth¡lcarbod¡¡m¡da (2.36 g, 12.30 mmol), 1-hydroxybenzotr¡azole (1.66 g, 12.30 mmol) and trylamine (7 ml, 49.2 mmol) successively. The reaction mixture was stirred for 16 hours and then added with 100 ml of ethyl acetate and 50 ml of water. The organic phase was concentrated under reduced pressure. The residues were purified via TLC with an elution system A to obtain the title compound, 2- (di-fluoromethyl) -5 - (((2-fluoro- Ethyl 14a 2-methylpropano (1) amine) methyl) nicotinate (1.6 g, 61.3%) as a yellow solid. MS m / z (ESI): 319.1 [M + 1]

Stage 2

2- (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín¡co acid

2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) ethyl nitrate was added 14a (1.6 g, 5.03 mmol) in 50 ml 1,4-dixane, and then lithium hydroxide hydrate ( 529 mg, 12.6 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residues were added with 5 ml of water, and then adjusted to pH 3 by 5 M hydrochloric acid. Much solid was collected from the reaction solution and then withdrew by filtration. The filtrate was extracted with ethyl acetate (50 mlx3). The organic phases were combined and concentrated under reduced pressure. The residues were combined with the above filter cake, and then washed with water to obtain the title compound, 2- (di-fluoromethyl) -5 - ((( 2-fluoro-2-methylpropanol) amine) methyl) ncotine 14b (500 mg, 34.2%) as a white solid.

MS m / z (ESI): 291.1 [M + 1]

Stage 3

N- (2- (4-Chlorophenyl) -1-methyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2 -metal-propane-l) amine) -methyl) ncotanamide 1-Ethyl-2- (4-chlorophenyl) -5-amine-1H-andol 10c (100 mg, 0.37 mmol), 2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propane) am ¡No) met¡l) n¡cotín¡co 14b (107 mg, 0.37 mmol), 1-eth¡l- (3-d¡met¡lam¡nopropyl) carbod¡¡m hydrochloride It gives (142 mg, 0.74 mmol) and 1-hydroxybenzotrazole (191 mg, 1.48 mmol) in 5 ml of N, N- d, methylformamide, successively. The reaction mixture was heated to 70 ° C and then stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, N- (2- (4-chlorophenyl) - 1-methyl-1H-andol-5-¡l) -2- (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) met¡l) n¡cotam¡da 14 (40 mg, 19.9%) as a solid of White color.

MS m / z (ESI): 543.3 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.60 (s, 1H), 8.87 (s, 1H), 8.69 (m, 1H), 8.04-8.02 (m, 2H) , 7.60-7.58 (m, 4H), 7.54- 7.53 (m, 1H), 7.43-7.42 (m, 1H), 7.19 (t, 1H), 6, 59 (s, 1H), 4.48-4.46 (m, 2H), 4.24-4.19 (m, 2H), 1.54-1.48 (d, 6H), 1.26- 1.15 (m, 3H).

Example 15

2- (D¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -N- (1-methyl-2- ( 4- (tr¡fluoromethyl) phen¡l) -1H-¡ndol-5-¡l) nicot¡nam¡da

1-methyl-5-amine-2- (4- (trifluoromethyl) phenyl) -1H-indol 9c (50 mg, 0.17 mmol) was dissolved, 2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) n¡cotín¡co 14b (50 mg, 0.17 mmol), 1-ethyl- (3-d¡methylamnopropyl) -3carbod¡¡m¡ hydrochloride (55 mg, 0.29 mmol), 1-h¡ drox¡benzotr¡azole (2.3 mg, 0.017 mmol) and W, A / -d¡¡soprop¡l-ethylamine (44 mg, 0.34 mmol) in 5 ml of W, A / - d¡met¡lformam¡da successively. The reaction mixture was heated to 70 ° C and then stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2- (di-fluoromethyl) -5- ( ((2-fluoro-2-methylpropano¡l) am¡no) methyl) -W- (1-methyl-2- (4- (tr¡fluoromethyl) phen¡l) -1H -¡Ndol-5-¡l) n¡cot¡nam¡da 15 (4 mg, 4.2%) as a light yellow solid.

MS m / z (ESI): 563.1 [M + 1]

1H NMR (400 MHz, DMSO-d6): 8 10.62 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7, 90-7.85 (m, 4H), 7.56-7.54 (m, 1H), 7.47-7.44 (m, 1H), 7.20 (s, 1H), 6.75 ( s, 1H), 4.48-4.46 (m, 2H), 3.80 (s, 3H), 1.54-1.48 (d, 6H).

Example 16

2-Chloro-N- (2- (4-chlorophenyl) ¡ndazol-5-¡l) -5 - ((2,2-d¡met¡lpropano¡lam¡no) methyl) benzam¡da

Stage 1

2- (4-Chlorophenyl) -5-nitro-indazole

Sodium nitrate (1.6 g, 19.2 mmol) in 10 ml of sulfuric acid was added in an ice-cold water bath. Then 2- (4-chlorophenyl) -2H-indazole 16a (2.2 g, 9.6 mmol) was added portionwise. The reaction mixture was then heated to 70 ° C and stirred for 1 hour. The reaction mixture was poured into 30 ml of ice-cold water and adjusted to pH> 7 by saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (40 mlx3). The organic phase was combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, the residues were purified by silica gel column chromatography with elution system B to obtain the title compound, 2- (4-chlorophenyl) -5-nitro-2H-indazole 16b ( 500 mg, 19.2%) as a yellow solid.

MS m / z (ESI): 274.0 [M + 1]

Stage 2

2- (4-Chlorophenyl) -5-amino-indazole

2- (4-chlorophenyl) -5-nitro-indazole 16b (500 mg, 1.8 mmol) was dissolved in 20 ml of tetrahydrofuran, and then added with Raney nickel (50 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filter cake was washed with ethyl acetate (5 mlx3). The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-chlorophenyl) -5-amino-indazole 16c (200 mg, 45%) as a brown solid.

MS m / z (ESI): 244.1 [M + 1]

Stage 3

2-Chloro-W- (2- (4-chlorophenyl) -2H-indazol-5-yl) -5 - ((2,2-dimethylpropanoylamino) methyl) benzamide

2- (4-chlorophenyl) -5-amino-indazole 16c (200 mg, 0.37 mmol), 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (300 mg, 1.04 mmol) and W, A / -diisopropylethylamine (300 mg, 2.32 mmol) in 10 ml of dichloromethane successively. The resulting mixture was stirred for 1 hour and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-A / - (2- (4-chlorophenyl) -2H-indazol-5-yl) - 5 - ((2,2-dimethylpropanoylamino) methyl) benzamide 16 (5 mg, 1.3%) as a light yellow solid.

MS m / z (ESI): 495.1 [M + 1]

1H NMR (400 MHz, DMSO-cfe): 810.56 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.19-8.11 (m, 3H) , 7.73-7.66 (m, 3H), 7.51 (m, 1H), 7.45-7.44 (m, 2H), 7.36-7.34 (m, 1H), 4 , 31-4.30 (m, 2H), 1.14 (s, 9H)

Example 17

2- (Difluoromethyl) -N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5 - (((2-fluoro-2-methyl

propano¡l) am¡no) met¡l) n¡cot¡nam¡da

1-Ethyl-5-amine-2- (4- (trifluoromethyl) phenyl) -1H-andol 1k (105 mg, 0.34 mmol) was dissolved, 2- (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín¡co 14b (100 mg, 0.34 mmol), 1-ethyl- (3-dimetilalamnopropyl) carbodiumhydrochloride (97 mg, 0.51 mmol), 1-hydrox ¡Benzotrazole (4.6 mg, 0.034 mmol) and N, N- d¡¡soprop¡let¡lam¡na (88 mg, 0.68 mmol) in 5 ml of N, Nd¡met¡lformam¡da successively. The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2- (di-fluoromethyl) -N- ( 1-ethyl-2- (4- (trifluoromethyl) phenyl) -1 H-in dol-5-l) -5 - (((2-fluoro-2-methyl -propanol) amino) methyl) nicotamide 17 (20 mg, 25.5%) as a yellow solid.

MS m / z (ESI): 577.3 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.60 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.90-7.88 (m, 2H), 7.82-7.80 (m, 2H), 7.58-7.56 (m, 1H), 7.45-7 , 43 (m, 1H), 7.32 (t, 1H), 6.69 (s, 1H), 4.47-4.46 (m, 2H), 4.28-4.26 (m, 2H ), 1.53-1.48 (d, 6H), 1.22-1.09 (m, 3H).

Example 18

N- (2- (4-Chlorophenyl) -1-methyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2 -meth¡l-propane¡l) am¡no) metal) n¡cot¡nam¡da

2- (4-chlorophenyl) -1-methyl-5-amino-1H-andol 13b (45 mg, 0.18 mmol), acid 2- (d ¡Fluorometal) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín¡co 14b (51 mg, 0.18 mmol), chlorh 1-ethyl- (3-d¡meth¡lam¡nopropyl) carbod¡¡m¡da (51 mg, 0.26 mmol), 1-hydroxybenzotr¡azole (24 mg , 0.18 mmol) and tri-ethylamine (71 mg, 0.70 mmol) in 5 ml of N, N- di-methylformamide successively. The resulting mixture was stirred for 3 hours and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, N- (2- (4-chlorophenyl) - 1-methyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methylpropano¡l) am¡no) methyl l) Nitrogen 18 (43 mg, 46.2%) as a light yellow solid.

MS m / z (ESI): 529.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.60 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.04 (d, 2H), 7.62 (dd, 4H), 7.47 (dd, 2H), 7.20 (t, 1H), 6.64 (s, 1H), 4.47 (d, 2H), 3.76 (s, 3H) , 1.54 (s, 3H), 1.48 (s, 3H).

Example 19

N- (2- (2-Chlorophenyl) -1-ethyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2 -meth¡l-propane¡l) am¡no) metal) n¡cot¡nam¡da

Stage 1

2- (2-Chlorophenyl) -1-ethyl-5-nitro-1H-andol

1-Ethyl-5-nitro-1H-indol was dissolved 1h (1.0 g, 5.3 mmol) in 10 ml of N, Nd¡metalacetamide, and then 1-chloro-2-iodo-benzene 19a (1.25 g, 5.3 mmol), triphenylphosphine (300 mg, 1.1 mmol), palladium acetate ( 120 mg, 0.53 mmol) and cesium acetate (2.1 g, 11 mmol) successively. The reaction mixture was heated to 140 ° C, and then stirred for 18 hours under an atmosphere of argon. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system B to obtain the title compound, 2- (2-chlorophenyl) -1-ethyl-5-nitro-1H-indol 19b (300 mg, 18.9%) as a yellow solid ¡Llo.

MS m / z (ESI): 301.3 [M + 1]

Stage 2

2- (2-Chlorophenyl) -1-ethyl-1H-andol-5-amine

2- (2-chlorophenyl) -1-ethyl-5-nitro-1H-indole 19b (300 mg, 1.0 mmol) was dissolved in 10 ml of tetrahydric mixture drofuran and methanol (V: V = 1: 1), and then added with Raney nickel (50 mg). The reaction mixture was stirred for 2 hours in a hydrogen atmosphere. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (2-chlorophenyl) -1-ethyl-1H-indol-5-amine 19c ( 270 mg) in the form of a yellow solid, which was used in the next stage without additional purification.

MS m / z (ESI): 271.1 [M + 1]

Stage 3

N- (2- (2-Chlorophenyl) -1-ethyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2 -metal-propanoyl) amine) methyl) n¡cot¡nam¡da 2- (2-chlorophenyl) -1-ethyl-1H-andol was dissolved -5-amine 19c (80 mg, 0.30 mmol), acid 2- (di-fluoromethyl) -5 - (((2-fluoro-2-methyl-propane) am ¡No) met¡l) n¡cotín¡co 14b (86 mg, 0.30 mmol), 1-eth¡l- (3-d¡met¡lam¡nopropyl) carbod¡¡m hydrochloride Da (115 mg, 0.60 mmol), 1-hydroxybenzotrazole (40 mg, 0.30 mmol) and triethylamine (118 mg, 1.17 mmol) in 5 mL of N, N- dimethylformamide successively. The reaction mixture was heated to 40 ° C and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, W- (2- (2-chlorophenyl) -1-ethyl -1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinamide 19 (10 mg, 14.3%) as a solid of yellow color. MS m / z (ESI): 543.9 [M + 1]

1H NMR (400MHz, DMSO-da): 810.59 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.02 (d, 2H), 7.65 (d, 1H), 7.52-7.49 (m, 3H), 7.42 (d, 1H), 6.48 (s, 1H), 4.46 (d, 2H), 3.99- 3.97 (m, 2H), 2.88 (s, 1H), 2.73 (s, 1H), 1.53 (s, 3H), 1.46 (s, 3H), 1.09 (t , 3H)

Example 20

N- (2- (3-Chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide

Stage 1

2- (3-Chlorophenyl) -1-ethyl-5-nitro-1H-indole

1-Ethyl-5-nitro-1H-indole was dissolved 1h (1.0 g, 5.3 mmol) in 10 ml of A /, W-dimethylacetamide, and then added with 1-chloro-3-iodo-benzene 20a (1.4 g, 5.8 mmol), triphenylphosphine (276 mg, 1.1 mmol), palladium acetate (119 mg, 0.53 mmol) and cesium acetate (2.0 g, 11 mmol) successively . The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system C to obtain the title compound, 2- (3-chlorophenyl) -1-ethyl-5- nitro-1H-indole 20b (120 mg, 7.6%) as a yellow solid.

MS m / z (ESI): 301.1 [M + 1]

Stage 2

2- (3-Chlorophenyl) -1-ethyl-1H-indole-5-amine

2- (3-chlorophenyl) -1-ethyl-5-nitro-1H-indole 20b (50 mg, 0.17 mmol) was dissolved in 10 ml of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) and then it was added with Raney nickel (5 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (3-chlorophenyl) -1-ethyl-1H-indole-5-amine 20c (45 mg) as a red oil, the which was used in the next step without further purification.

MS m / z (ESI): 271.1 [M + 1]

Stage 3

W- (2- (3-Chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 2- (3-chlorophenyl) -1-ethyl-1H-indole-5-amine 20c (45 mg, 0.17 mmol), 2- (difluoromethyl) -5 - (((2-fluoro-2- methylpropanoyl) amino) methyl) nicotinic 14b (49 mg, 0.17 mmol), 1-ethyl- (3-dimethylaminenopropyl) carbohydrate hydrochloride (48 mg , 0.25 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol) and triethylamine (68 mg, 0.66 mmol) in 5 ml of N, N- dimethylformamide successively. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, N- (2- (3-chloropheml) -1-ethyl-1H-indol-5-yl) -2 - (Difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinamide 20 (45 mg, 50% over two steps) as an off-white solid. MS m / z (ESI): 543.1 [M + 1]

1H NMR (400MHz, DMSO-d6): 810.62 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.03 (d, 2H), 7.57 -7.55 (m, 6H), 7.43 (t, 1H), 7.19 (s, 1H), 6.64 (d, 2H), 4.49-4.47 (m, 2H), 1.54 (s, 3H), 1.49 (s, 3H), 1.19 (t, 3H).

Example 21

N- (2- (4-Chlorofeml) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((1- (tnfluoromethyl) cyclopropanecarboml) amino) methyl) mcotinamide

Stage 1

Ethyl 2- (Difluoromethyl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinate

Ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinate hydrochloride 1d (4.0 g, 13.2 mmol) was dissolved in 50 ml of N, N- dimethylformamide, and then added with 1- (trifluoromethyl acid ) cyclopropane-1-carboxylic 21a (2.03 g, 13.2 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.07 g, 26.4 mmol), 1-hydroxybenzotriazole (178 mg, 1.32 mmol) and triethylamine (5.3 g, 52.8 mmol) successively. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The residues were washed with ethyl acetate (50 ml) and water (50 ml), dried to obtain the title compound, 2- (difluoromethyl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) Crude ethyl nicotinate 21b (4.83 g) as a brown oil, which was used in the next step without further purification.

MS m / z (ESI): 367.1 [M + 1]

Stage 2

2- (Difluoromethyl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinic acid

Ethyl 2- (difluoromethyl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinate 21b (4.83 g, 13.2 mmol) was dissolved in 150 ml of 1,4-dioxane mixture and water (V: V = 2: 1), and then added with lithium hydroxide hydrate (1.38 g, 33.0 mmol). The reaction mixture was stirred for 1 hour. The ethanol was removed under reduced pressure, and the residues were adjusted to pH 4-5 by 6M hydrochloric acid. A large amount of solid precipitated, and 100 ml of ethyl acetate was added. The solid was filtered off and directed to obtain the title compound, 2- (difluoromethyl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) -methyl) nicotinic acid 21c (2.0 g, 44, 8% for two stages) as a white solid.

MS m / z (ESI): 339.1 [M + 1]

Stage 3

W- (2- (4-Chlorophenyl) -1-methyl-1H-andol-5-¡l) -2- (d¡fluoromethyl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinamide

2- (4-chlorophenyl) -1-methyl-5-amino-1H-andol 13b (45 mg, 0.17 mmol), acid 2- (d ¡Fluorometh¡l) -5 - (((1- (tr¡fluorome¡l) c¡dopropanecarbon¡l) am¡no) methyl) n¡cotín¡co 21c (59 mg, 0.17 mmol), 1-ethyl- (3-dimethylamnopropyl) hydrochloride (51 mg, 0.26 mmol), 1-hydroxybenzotrazole (24 mg, 0.17 mmol) and tri-ethylamine (71 mg, 0.70 mmol) in 5 ml of W, A / -d¡methylamine, successively. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, W- (2- (4-chlorophenyl) - 1-methyl-1H-andol-5-¡l) -2- (d¡fluorometh¡l) -5 - (((1- (tr¡fluorometh¡l) cyclopropanecarbon¡l) am¡no ) methyl) nitrogen 21 (20 mg, 20%) as a light yellow solid.

MS m / z (ESI): 577.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.61 (s, 1H), 8.67 (s, 1H), 8.59-8.57 (m, 1H), 8.03 (d, 2H) , 7.62 (dd, 4H), 7.47 (dd, 2H), 7.19 (t, 1H), 6.64 (s, 1H), 4.46 (d, 2H), 3.76 ( s, 3H), 1.28-1.26 (m, 4H).

Example 22

2-Chloro-5 - ((2,2-d¡meth¡lpropano¡lam¡no) methyl) -A / - (2- (4- (tr¡fluorometh¡l) phen¡l) benzo [d ] oxazol-5-¡l) benza ^{iT i} ¡da

Stage 1

5-Nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole

4- (tri-fluoromethyl) benzoic acid 22a (2.0 g, 10.5 mmol) was dissolved in 14 ml of polyphosphoric acid and then added or with 2-amino-4-nitrophenol (1.62 g, 10.5 mmol). The reaction mixture was heated to 120 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature and then poured into 500 ml of water. The solution was adjusted to pH 7 by adding sodium hydroxide in portions and then extracted with ethyl acetate (500 mlx3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound, 5-nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole 22b (1 , 5 g) in the form of a brown solid, which was used in the next stage without additional purification.

Stage 2

2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine

5-nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole 22b (170 mg, 0.55 mmol) was dissolved in 10 ml of tetrah mixture Drofuran and methanol (V: V = 1: 1), and then added with Raney nickel (20 mg). The reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (150 mg) as a brown solid, which was used in the next step without further purification. MS m / z (ESI): 279.1 [M + 1]

Stage 3

2-Chloro-5 - ((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide

2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (50 mg, 0.18 mmol) was dissolved in 10 ml of tetrahydrofuran, and then added dropwise with trifluoroacetic acid (54 μl , 0.39 mmol) and 2 ml of a solution of 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (52 mg, 0.18 mmol) in tetrahydrofuran. The resulting mixture was stirred for 1 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain a solid, which was added with 10 ml of ethyl acetate and filtered. The filter cake was dried to obtain the title compound, 2-chloro-5 - ((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole-5 -yl) benzamide 22 (15 mg, 15.3% over two steps) as a light yellow solid.

MS m / z (ESI): 530.3 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.41 (s, 1H), 8.19 (t, 1H), 8.11 (s, 1H), 7.91-7.87 (d, 2H ), 7.83-7.79 (d, 2H), 7.59- 7.53 (d, 2H), 7.53-7.48 (d, 2H), 7.48-7.41 (m, 1H), 4.29-4.22 (m, 2H), 1.13 (s, 9H).

Example 23

12- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-¡l) nicot¡nam¡da

2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (50 mg, 0.18 mmol) was dissolved in 10 ml of N, N- dimethylformamide, and then 2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinic acid 14b (52 mg, 0.18 mmol), 1-ethyl- (3-dimethylaminopropyl hydrochloride) was added ) carbodiimide (75 mg, 0.39 mmol), 1-hydroxybenzotriazole (2.4 mg, 0.02 mmol) and triethylamine (73 mg, 0.72 mmol) successively. The resulting mixture was heated to 70 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain a solid. The solid was added with 10 ml of diethyl ether and filtered. The filter cake was dried to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 23 (10 mg, 10.1%) as a light yellow solid.

MS m / z (ESI): 551.3 [M + 1]

1H NMR (400MHz, DMSO-da): 810.60 (s, 1H), 8.69 (s, 1H), 8.45 (t, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.92-7.86 (d, 2H), 7.85-7.79 (d, 2H), 7.61-7.56 (d, 1H), 7.46-7 , 42 (d, 1H), 7.20 (t, 1H), 4.31-4.21 (m, 2H), 2.49-2.40 (m, 1H), 1.09-1.02 (d, 6H).

Example 24

2- (Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide

Stage 1

W- (2-n¡trobenz¡l) -4- (tr¡fluorometh¡l) an¡l¡na

4-Amnobenzotrofluoride 24a (2.35 g, 14.56 mmol) was dissolved in 50 ml of 1,2-dichloroethane and then added with 2-nitrobenzaldehyde 24b (2.0 g, 13 , 23 mmol). The resulting mixture was stirred for 0.5 hour, and then added with sodium triacetoxyboronhydride (5.6 g, 26.46 mmol) and stirred for another 16 hours. The reaction mixture was added with 100 ml of dichloromethane and 100 ml of water. The organic phase was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system C to obtain the compound of the title, W - ('2-nitrobenzl) -4- (trifluoromethyl) anine 24c (3.5 g, 89.4%) as an oil of yellow color.

MS m / z (ESI): 297.1 [M + 1]

Stage 2

2- (4- (Trifluoromethyl) phenil) -2H-ndazole

Cnc powder (1.73 g, 27.04 mmol) was added in 50 ml of tetrahydrofuran, and then added with tetanus tetrachloride (2.57 g, 13, 55 mmol). The reaction mixture was heated to 70 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature and adjusted to pH 8 by trielamine. W- (2-nitrobenzyl) -4- (trifluoromethyl) anin 24c (1.0 g, 3.38 mmol) was dissolved in 20 ml of tetrahydrogen drofuran and then in the resulting mixture above. The reaction mixture was continuously stirred for another 30 min and then adjusted to pH 3 by 6 M hydrochloric acid. The solution was extracted with dichloromethane (100 ml x 3) . The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system C to obtain the compound of titer, 2- (4- (trifluoromethyl) phenyl) -2H-ndazole 24d (100 mg, 11.3%) as a white solid.

MS m / z (ESI): 263.1 [M + 1]

Stage 3

5-Nitro-2- (4- (tnfluoromethyl) phenyl) -2H-ndazole

Sodium nitrate (29 mg, 0.67 mmol) in 1 ml sulfuric acid was added in a ice bath, and then added in portions with 2- ( 4- (tri-fluoromethyl) phenyl) -2H-ndazole 24d (50 mg, 0.19 mmol). The reaction mixture was heated to 70 ° C and stirred for 1 hour. The reaction mixture was poured into 30 ml ice-cold water and adjusted to pH> 7. The solution was extracted with ethyl acetate (40 mlx3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 5-nitro-2- (4- (trifluoromethyl) phenyl) -2H -indazole 24e (30 mg, 25.6%) as a yellow solid.

MS m / z (ESI): 308.1 [M + 1]

Stage 4

2- (4- (Trifluoromethyl) phenyl) -2H-indazol-5-amine

5-Nitro-2- (4- (trifluoromethyl) phenyl) -2H-indazol 24e (30 mg, 0.098 mmol) was dissolved in 10 ml of mixture of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (3 mg). The reaction mixture was stirred for 1 hour under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4- (trifluoromethyl) phenyl) -2H-indazol-5-amine 24f (27 mg) as a light yellow solid, the which was used in the next step without further purification. MS m / z (ESI): 278.1 [M + 1]

Stage 5

2- (Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) -W- (2- (4- (trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide

2- (4- (Trifluoromethyl) phenyl) -2H-indazol-5-amine 24f (27 mg, 0.098 mmol), 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid If (27 mg, 0.10 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (29 mg, 0.15 mmol) and 1-hydroxybenzotriazole (14 mg, 0.10 mmol) in 5 ml of W, A / -dimethylformamide successively. The resulting mixture was heated to 40 ° C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain a solid. The solid was added with 20 ml of dichloromethane and stirred for 20 min. The mixture was filtered and the filter cake was washed with dichloromethane (5 mlx3) and dried to obtain the title compound, 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) -W- (2- ( 4- (trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide 24 (27 mg, 50.9%) as a white solid.

MS m / z (ESI): 532.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.78 (s, 1H), 9.25 (s, 1H), 8.70 (s, 1H), 8.47 (t, 1H), 8, 38-8.33 (m, 3H), 8.08-7.97 (m, 3H), 7.76 (d, 1H), 7.49 (d, 1H), 7.19 (t, 1H) , 4.44 (d, 2H), 2.49-2.41 (m, 1H), 1.06 (d, 6H).

Example 25

2-Chloro-5 - ((2,2-dimethylpropanoylamino) methyl) -A / - (2- (4- (trifluoromethyl) phenyl) isoindolin-5-yl) benzamide

Stage 1

6-Nitro-2- (4- (trifluoromethyl) phenyl) isoindolin-1-one

4-Aminobenzotrifluoride 24a (193 mg, 1.2 mmol) was dissolved in 3 ml of ethanol, and then with methyl 2- (bromomethyl) -5-nitro-benzoate 25a (274 mg, 1.0 mmol) and W, A / -diisopropylethylamine (258 mg, 2.0 mmol). The reaction mixture was heated to 110 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was dried to obtain the title compound, 6-nitro-2- (4- (trifluoromethyl) phenyl) isoindolin-1-one 25b (70 mg, 21.7%) as a yellow solid .

MS m / z (ESI): 321.0 [M-1]

Stage 2

6-Amino-2- (4- (trifluoromethyl) phenyl) isoindolin-1-one

6-Nitro-2- (4- (trifluoromethyl) phenyl) isoindolin-1-one 25b (70 mg, 0.098 mmol) was dissolved in 10 ml of tetrahydrofuran and methanol mixture (V: V = 1: 1) and then added with Raney nickel (7 mg). The reaction mixture was stirred for 1 hour under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 6-amino-2- (4- (trifluoromethyl) phenyl) isoindolin-1-one 25c (64 mg) as a white solid, the which was used in the next step without further purification.

MS m / z (ESI): 293.1 (M + 1)

Stage 3

2- (4- (Trifluoromethyl) phenyl) isoindolin-5-amine

6-amino-2- (4- (trifluoromethyl) phenyl) isoindolin-1-one 25c (64 mg, 0.22 mmol) was dissolved in 10 ml of tetrahydrofuran and then added with lithium aluminum hydride (51 mg, 1.32 mmol). The reaction mixture was heated to 65 ° C and stirred for 16 hours. The reaction mixture was added with 0.1 ml of sodium hydroxide solution (15%) and 0.4 ml of water followed by magnesium sulfate and stirred for another 5 min. The mixture was filtered and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (4- (trifluoromethyl) phenyl) isoindolin-5-amine 25d (11mg, 18.0%) as a gray solid.

MS m / z (ESI): 279.1 [M + 1]

Stage 4

2-Chloro-5 - ((2,2-d¡meth¡lpropano¡lam¡no) methyl) -N- (2- (4- (tr¡fluorometh¡l) phen¡l) ¡so¡ndol ¡N-5-¡l) benzam¡da

2- (4- (trifluoromethyl) phenl) sondolin-5-amine 25d (11 mg, 0.04 mmol), 2-chloro- 5 - ((2,2-d¡methylpropanolamno) methyl) benzo¡co 2a (11 mg, 0.04 mmol), 1-ethyl- (3-d hydrochloride ¡Meth¡lam¡nopropyl) carbod¡¡m¡da (12 mg, 0.06 mmol), 1-hydroxybenzotrazole (6 mg, 0.04 mmol) and tr¡et¡lam¡ na (17 mg, 0.16 mmol) in 5 ml of N, N- d, methylformamide, successively. The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2-chloro-5 - ((2,2-d ¡Methylpropano¡lam¡no) methyl) -N- (2- (4- (tr¡fluorome¡l) phen¡l) ¡so¡ndol¡n-5-¡l) benzam¡da 25 ( 6 mg, 28.6%) as a white solid. Em m / z (ENI): 530.1 [M + 1]

1H NMR (400 MHz, DMSO-d6): 8 10.61 (s, 1H), 8.18 (t, 1H), 7.89 (s, 1H), 7.60-7.50 (m, 4H ), 7.42-7.34 (m, 3H), 6.80 (d, 2H), 4.68 (d, 4H), 4.30 (d, 2H), 1.14 (s, 9H) .

Example 26

2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -N- (2- (4- (tr¡fluoromet ¡L) fen¡l) ¡so¡ndol¡n-5-¡l) n¡cot¡nam¡da

2- (4- (trifluoromethyl) phenl) sondolin-5-amine 25d (63 mg, 0.23 mmol) was dissolved in 5 ml of N, Nd¡met¡lformamid and added with acid 2- (d¡fluorome¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) met ¡L) n¡cotín¡co 14b (66 mg, 0.23 mmol), 1-eth¡l- (3-d¡met¡lam¡nopropyl) carbohydrate (67 mg, 0.35 mmol), 1-hydroxybenzotrazole (27 mg, 0.23 mmol) and tritlamine (93 mg, 0.92 mmol) successively. The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2- (di-fluoromethyl) -5- ( ((2-fluoro-2-methylpropano¡l) am¡no) methyl) -N- (2- (4- (tr¡fluorome¡l) phen¡l) ¡so¡ndol¡n-5 -¡L) n¡cot¡nam¡da 26 (50 mg, 39.7%) as a white solid.

MS m / z (ESI): 551.1 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.79 (s, 1H), 8.87 (s, 1H), 8.70 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.57 (d, 3H), 7.42 (d, 1H), 7.16 (t, 1H), 6.80 (d, 2H), 4.69 (d, 4H) , 4.66 (d, 2H), 1.53 (s, 3H), 1.48 (s, 3H).

Example 27

2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) -N- (1- (2-methox¡et¡ l) -2- (4- (tr¡fluorometh¡l (phen¡l) -1H-¡ndol-5-¡l (n¡cot¡nam¡da

Stage 1

1- (2-Methoxy ethyl-5-mtro-2- (4- (tnfluoromethyl) feml) -1H-andol

1- (2-methoxyethyl) -5-mtro-1H-indole 27a (2.2 g, 10 mmol, prepared according to the method disclosed in patent application "US20090076275") was dissolved in 10 ml of WA- dimethylacetamide, and then added with 1-iodo-4- (trifluoromethyl) benzene 1i (2.7 g, 10 mmol), triphenylphosphine (564 mg, 2.0 mmol), palladium acetate (225 mg, 1.0 mmol) ) and cesium acetate (3.8 g, 20 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and the residues were washed with ethyl acetate (5 mlx3). The filtrate was concentrated under reduced pressure, the residues were purified by column chromatography on silica gel with elution system C to obtain the title compound, 1- (2-methoxyethyl-5-nitro-2- (4 - (t ^ fluoromethyl) phenil) -1H-indole 27b (300 mg, 8.2%) as a yellow solid.

MS m / z (ESI): 365.1 (M + 1)

Stage 2

1- (2-Methox¡et¡l-5-am¡no-2- (4- (t ^ fluorometh¡l) phen¡l) -1H-andol

1- (2-methoxyetil-5-nitro-2- (4- (t-fluoromethyl) phenil) -1H-andol 27b (100 mg, 0.27 mmol) was dissolved in 20 ml of mixture of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (10 mg) .The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom and the filter cake was washed with ethyl acetate (30 ml) .The filtrate was concentrated under reduced pressure to obtain the crude title compound, 1- (2-methoxyetil-5-am¡ no-2- (4- (trifluoromethyl) phenyl) -1H-indole 27c (90 mg) as a yellow oil, which was used in the next step without further purification.

MS m / z (ESI): 335.1 [M + 1]

Stage 3

2- (D¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) A- (1- (2-methoxyet¡l ) -2- (4- (t ^ fluoromethyl) phenyl) -1H-andol-5-iOnicotinamide

1- (2-methoxy ethyl-5-amine-2- (4- (trifluoromethyl) phenyl) -1H-andol 27c (150 mg, 0.44 mmol) were dissolved , 2- (Difluoromethyl ^ - ^^ - fluoro ^ -metN-propanoiOamino ^ ethiOnicotmic acid 14b (128 mg, 0.44 mmol), 1-ethyl- (3-dimethylaminopropylcarbodiimide hydrochloride (169 mg, 0.88 mmol), 1-hydroxybenzotriazole (6 mg, 0.04 mmol) and triethylamine (178 mg, 1.76 mmol) in 10 ml of WA-dimethylacetamide successively The reaction mixture was heated to 75 ° C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro- 2-methyl-propano¡l) amino) methyl) A- (1- (2-methox¡et¡l) -2- (4- (t ^ fluoromethyl) phen¡l) - 1H-ndol-5-l) n¡cot¡nam¡da 27 (60 mg, 22.4%) in the form of a yellow solid.

MS m / z (ESI): 607.3 [M + 1]

1H NMR (400 MHz, DMSO-da): 8 10.624 (s, 1H), 8.879 (s, 1H), 8.692 (s, 1H), 8.021-8.062 (m, 2H), 7.871-7.921 (m, 4H) , 7.592-7.614 (m, 1H), 7.421-7.438 (m, 1H), 7.192-7.416 (m, 1H), 6.689 (s, 1H), 4.376-4.815 (m, 4H), 3.548-3.575 (m, 2H), 3.058-3.575 (s, 3H), 1.443-1.541 (d, 6H)

Example 28

2- (D¡fluorometh¡l) -N- (1-eth¡l-2- (3 - (tr¡fluorome¡l) phen¡l) -1H-¡ndol-5-¡l) -5- (((2-fluoro-2-methyl-propane) amine) methyl) -nicotinamide

Stage 1

1-Ethyl-5-nitro-2- (3- (trifluoromethyl) phenyl) -1H-andol

1-Ethyl-5-nitro-1H-indole 1h (500 mg, 2.63 mmol) was dissolved in 5 ml of N, N-dimethylacetamide, and then added with 1-iodo-3- (trifluoromethyl) benzene 28a ( 860 mg, 3.16 mmol), triphenylphosphine (140 mg, 0.53 mmol), palladium acetate (119 mg, 0.13 mmol) and cesium acetate (2.0 g, 11 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 16 hours under an argon atmosphere. The reaction solution was added with 40 ml of water and extracted with ethyl acetate (40 mlx2). The organic phase was combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residues were purified by column chromatography on silica gel with elution system C to obtain the title compound, 1-ethyl-5-nitro-2- (3- (tr Fluoromethyl) phenl) -1H-indole 28b (100 mg, 11.4%) as a yellow solid.

MS m / z (ESI): 335.1 [M + 1]

Stage 2

1- Ethyl-5-amino-2- (3- (trifluoromethyl) phenyl) -1H-indole-1-ethyl-5-nitro-2- (3- (tri fluoromethyl) phenyl) -1H-indole 28b (110 mg, 0.33 mmol) in a mixture of 8 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (30 mg ). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the crude title compound, 1-ethyl-5-amino-2- (3- (trifluoromethyl) phenyl). -1H-indole-28c (100 mg) as a light yellow solid, which was used in the next step without further purification. MS m / z (ESI): 305.1 [M + 1]

Stage 3

2- (D¡fluoromethyl) -N- (1-ethyl-2- (3- (tr¡fluoromethyl) phen¡l) -1H-¡ndol-5-¡l) -5 - ((( 2-fluoro-2-methylpropanoyl) am¡no) methyl) nicot¡nam¡da

1-Ethyl-5-amino-2- (3- (trifluoromethyl) phenyl) -1 H-indole 28c (50 mg, 0.16 mmol), 2- (difluoromethyl) -5 - (((2- fluoro-2-methyl-propanoyl) amino) methyl) nicotinic 14b (50 mg, 0.16 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (70 mg, 0.33 mmol) and 1-hydroxybenzotriazole ( 25 mg, 0.16 mmol) in 3 ml of N, N- dimethylacetamide successively. The reaction mixture was heated to 40 ° C and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -N- (1-ethyl-2 - (3- (tnfluoromethyl) phenyl) -1H-indol-5-yl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide28 (20 mg, 21.1%) as yellow solid.

MS m / z (ESI): 575.5 [M-1]

1H NMR (400 MHz, DMSO-da): 8 10.59 (s, 1H), 8.85 (s, 1H), 8.67 (s, 1H), 8.03 (d, 2H), 7, 85-7.83 (m, 1H), 7.81-7.79 (m, 2H), 7.56 (d, 1H), 7.44 (d, 1H), 6.68 (s, 1H) , 4.46 (d, 2H), 4.22-4.18 (m, 2H), 2.87 (s, 1H), 2.72 (s, 1H), 1.52 (s, 3H), 1.46 (s, 3H), 1.22 (t, 3H)

Example 29

2- (D¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amine) methyl) -N- (2- (4- (tri-fluoromethyl ) fen¡l) benzofuran-5-¡l) n¡cot¡nam¡da

Stage 1

5-Nitro-2- (4- (trifluoromethyl) phenyl) benzofuran

A mixture of 6 ml of 1,4-dioxane and water (V: V = 5: 1) was dissolved 4- (trifluoromethyl) (pinacolboryl) benzene 29a (170 mg, 0.62 mmol), and then added with 2 -bromo-5-nitro-benzofuran 29b (100 mg, 0.43 mmol, prepared according to the method disclosed in "European Journal of Organic Chemistry, 2013, 2013 (9), 1644-1648"), [1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (30 mg, 0.04 mmol) and sodium carbonate (88 mg, 0.83 mmol). The reaction mixture was heated to 100 ° C and stirred for 16 hours under an argon atmosphere. The reaction solution was added with 50 ml of dichloromethane and filtered with celatom. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system C to obtain the title compound, 5-nitro-2- (4- (trifluoromethyl) phenyl) benzofuran 29c (80 mg) as a light yellow solid, which was used in the next step without further purification.

Stage 2

5-Amino-2- (4- (trifluoromethyl) phenyl) benzofuran

5-Nitro-2- (4- (trifluoromethyl) phenyl) benzofuran 29c (40 mg, 0.13 mmol) was dissolved in a mixture of 10 ml of tetrahydrofuran and water (V: V = 1: 1) and then added with Raney nickel (40 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the title compound, 5-amino-2- (4- (trifluoromethyl) phenyl) benzofuran 29d (36 mg) as a solid of light yellow color, which was used in the next step without further purification.

MS m / z (ESI): 278.2 [M + 1]

Stage 3

2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -N- (2- (4- (tr¡fluoromet ¡L) phen¡l) benzofuran-5-¡l) n¡cot¡nam¡da 5-am¡no-2- (4- (tr¡fluoromethyl) phen¡l) benzofuran 29d ( 33 mg, 0.12 mmol), 2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propanol) amine) methyl) n acid ¡Cotin¡co 14b (35 mg, 0.12 mmol), 1-ethyl- (3-d¡meth¡lam¡nopropyl) hydrochloride, carbod¡¡m¡da (45 mg, 0, 24 mmol) and 1-hydroxybenzotrazole (16 mg, 0.12 mmol) in 3 ml of N, N- d¡metalacetamide successively. The reaction mixture was heated to 40 ° C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -N- (2- (4- (trifluoromethyl) phenl) benzofuran-5-il) nicotamide 29 (20 mg, 30.3%) as a white solid. MS m / z (ESI): 550.3 [M + 1]

1H NMR (400MHz, DMSO-da): 810.7 (s, 1H), 8.71 (s, 1H), 8.49 (t, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.93-7.88 (m, 2H), 7.86-7.80 (m, 2H), 7.61-7.56 (m, 1H), 7.46-7 , 42 (m, 1H), 7.31-7.01 (m, 1H), 7.15 (s, 1H), 4.44-4.38 (m, 2H), 1.55-1.49 (m, 6H).

Example 30

2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) -N- (1-tetrahydrofuran-3-¡ l-2- (4- (tr¡fluoromethyl) phen¡l) -1H-¡ndol-5-¡l) n¡cot¡nam¡da

Stage 1

5-Nitro- (1-tetrahydrofuran-3-¡l) -1H-andol

5-Nitrondol 30a (810 mg, 5.0 mmol) was dissolved in 10 ml of N, Nd¡metalacetamide in a ice bath, and then added with sodium hydroxide (300 mg, 7.5 mmol). The reaction solution was warmed to room temperature and then stirred for 10 min. Tetrahydrofuran-3-lo methanesulfonate 30b (1.66 g, 10.0 mmol, prepared according to the method described in "Journal of Organico Chem¡stry, 2008, 73 (14 ), 5397-5409 ") and the mixture was heated to 50 ° C and stirred for 16 hours. The reaction mixture was added with 100 ml of water, and mixed well, then extracted with ethyl acetate (100 ml * 3). The organic phases were combined and washed with a saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound, 5-nitro-1-tetrahydrofuran-3-yl-1H-indole 30c (1.16 g) as a white solid, which was used in the next step without further purification.

MS m / z (ESI): 233.1 [M + 1]

Stage 2

5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole

5-Nitro-1- (tetrahydrofuran-3-yl) -1H-indole 30c (1.16 g, 5.0 mmol) was dissolved in 10 ml of N, N-dimethylacetamide, and then added with 1-iodo- 4- (trifluoromethyl) benzene 1i (1.36 g, 5.0 mmol), triphenylphosphine (282 mg, 1.0 mmol), palladium acetate (113 mg, 0.5 mmol) and cesium acetate (1.9 g, 10 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with a C elution system to obtain the title compound, 5-nitro-1- (tetrahydrofuran-3-yl) - 2- (4- (trifluoromethyl) phenyl) -1H-indole 30d (200 mg, 10.6%) as a yellow solid.

MS m / z (ESI): 377.1 [M + 1]

Stage 3

5-Amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole

5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) pheny) -1H-indole 30d (100 mg, 0.27 mmol) was dissolved in 10 ml of tetrahydrofuran, and then added with Raney nickel (10 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom and the filter cake was washed with ethyl acetate (30 ml). The filtrate was concentrated under reduced pressure to obtain the title compound, 5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 30e (85 mg, 92.4 %) as a yellow solid.

MS m / z (ESI): 347.1 [M + 1]

Stage 4

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) - 1H-indol-5-yl) nicotinamide

5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 30e (70 mg, 0.20 mmol), 2- (difluoromethyl) -5- acid were added (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinic 14b (58 mg, 0.20 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg, 0.30 mmol), 1 -hydroxybenzotriazole (3 mg, 0.02 mmol) and N, N- diisopropylethylamine (52 mg, 0.40 mmol) in 10 ml of N, N-dimethylacetamide successively. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro -2-methylpropanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide 30 (20 mg, 16, 1%) as a light yellow solid.

MS m / z (ESI): 619.2 [M + 1]

1H NMR (400 MHz, DMSO-cfe): 810.64 (s, 1H), 8.87 (s, 1H), 8.69 (t, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 8.01-7.91 (m, 2H), 7.78-7.76 (m, 2H), 7.72-7.69 (m, 1H), 7.40-7 , 39 (m, 1H), 7.18 (t, 1H), 6.65 (s, 1H), 5.13 (m, 1H), 4.68-4.67 (m, 2H), 4, 48-4.46 (m, 1H), 4.32-4.17 (m, 1H), 3.96-3.91 (m, 1H), 3.67-3.65 (m, 1H), 2.40-2.33 (m, 2H), 1.54-1.42 (d, 6H). Example 31

(S) -2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl ) phenyl) -1 H-indol-5-yl) nicotinamide

Stage 1

(S) -5-Nitro-1- (tetrahydrofuran-3-yl) -1 Hindol

5-Nitroindole 30a (9.0 g, 55.3 mmol) and cesium carbonate (36.0 g, 110.6 mmol) were dissolved in 100 ml of N, N- dimethylacetamide, and then added with ( R) Tetrahydrofuran-3-yl 31a (18.4 g, 110.6 mmol, prepared according to the method disclosed in "Nature Chemical Biology, 2008, 4 (11), 691-699"). The reaction mixture was heated to 70 ° C and stirred for 16 hours. The reaction solution was poured into 400 ml of ice-cold water. Much solid precipitated and was then filtered. The filter cake was dissolved in ethyl acetate and filtered. The filtrate was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound, (S) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 31b (12 g, 93.8%) as a solid. yellow.

MS m / z (ESI): 233.0 [M + 1]

Stage 2

(S) -5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1 H-indole

(S) -5-Nitro-1- (tetrahydrofuran-3-yl) -1H-indole 31b (2.0 g, 8.6 mmol) was dissolved in 15 ml of N, N-dimethyl-acetamide, and then added with 1-iodo-4- (trifluoromethyl) benzene 1i (2.58 g, 9.5 mmol), triphenylphosphine (450 mg, 1.7 mmol), palladium acetate (97 mg, 0.4 mmol) and acetate cesium (5.0 g, 25.9 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction solution was added with 200 ml of water and extracted with ethyl acetate (200 mlx2). The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system C to obtain the title compound, (S) -5-nitro-1- (tetrahydrofuran-3-yl ) -2- (4- (trifluoromethyl) phenyl) -1 H-indole 31c (200 mg, 5.3%) as a yellow solid. MS m / z (ESI): 377.1 [M + 1]

Stage 3

(S) -5-Amino-1- (tetrahydrofuran-3-¡l) -2- (4- (trifluoromethyl) phenyl) -1H-andol

(S) -5-nitro-1- (tetrahydrofuran-3-¡l) -2- (4- (trifluoromethyl) phenyl) -1 H-indole 31c (200 mg 0.53 mmol) in a mixture of 10 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (20 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the title compound, (S) -5-amino-1 - (- tetrahydrofuran-3-¡l) -2- (4- ( trifluoromethyl) phenyl) -1 H-indole 31d (130 mg, 70.7%) as a light yellow solid.

MS m / z (ESI): 347.2 [M + 1]

Stage 4

(S) -2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) -W- (1- (tetrah¡ drofuran-3-¡l) -2- (4- (trifluoromethyl) phen¡l) -1 H-indole-5-¡l) n¡cot¡namide

(S) -5-amino-1- (tetrahydrofuran-3-¡l) -2- (4- (trifluoromethyl) phenil) -1H-andol 31d (130 mg, 0 , 38 mmol), 2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropano) amine) methyl) ncotinic acid 14b (58 mg, 0 , 20 mmol), 1-ethyl- (3-dimethylamnopropyl) carbodimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxybenzotriazole (4 mg, 0.03 mmol) and triethylamine (139 mg, 1.38 mmol) in 5 ml of A /, W-dimethylacetamide successively. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system A to obtain the title compound, (S ) -2- (Difluoromethyl) -5 - (((2-fluoro-2-methylpropano¡l) amino) methyl) -A / - (1- (tetrahydrofuran-3-¡l) -2- (4- (tr¡fluoromethyl) phenyl) -1H-¡ndol-5-¡l) n¡cot¡nam¡da 31 (100 mg, 46.9%) as a colored solid White.

MS m / z (ESI): 619.3 [M + 1]

1H NMR (400MHz, DMSO-da): 810.63 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 8.12 (s, 1H), 8.01 -8.12 (d, 1H), 7.89-7.91 (d, 2H), 7.75-7.77 (d, 2H), 7.69-7.71 (d, 1H), 7 , 39-7.40 (d, 1H), 7.31 (t, 1H), 6.64 (s, 1H), 4.46-4.48 (d, 2H), 4.32-4.35 (m, 1H), 4.13-4.17 (m, 1H), 3.91-3.95 (m, 1H), 3.65-3.67 (m, 1H), 2.42-2 , 45 (m, 1H), 2.32-2.36 (m, 1H), 1.98-2.04 (m, 1H), 1.54 (s, 3H), 1.48 (s, 3H ).

Example 32

(ffl-2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) -N- (1- (tetrahydrofuran -3-¡l) -2- (4- (tr¡fluoromethyl) phenyl) -1 H-indole-5-¡l) n¡cotinam¡da

Stage 1

(R) -5-Nitro-1- (tetrahydrofuran-3-yl) -1 H-indole

5-Nitroindole 30a (5.0 g, 30.8 mmol) and cesium carbonate (20.0 g, 61.3 mmol) were dissolved in 70 ml of N, N- dimethylacetamide, and then added with ( S) -tetrahydrofuran-3-yl 32a (10.0 g, 60.2 mmol, prepared according to the method disclosed in "Nature Chemical Biology, 2008, 4 (11), 691-699"). The reaction mixture was heated to 70 ° C and stirred for 16 hours. The reaction solution was poured into 400 ml of ice-cold water. Much solid was precipitated and filtered. The filter cake was washed with water (50 mlx3), and dried to obtain the title compound, (R) -5-mtro-1- (tetrahydrofuran-3-N) -1 H-indole 32b (7.0 g) as a yellow solid, which was used in the next step without further purification.

MS m / z (ESI): 233.0 [M + 1]

Stage 2

(R) -5-Nitro-1 - (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1 H-indole

(R) -5-mtro-1- (tetrahydrofuran-3-N) -1 H-indole 32b (2.0 g, 8.6 mmol) was dissolved in 80 ml N, N-dimethylacetamide, and then added with 1-Iodo-4- (trifluoromethyl) benzene 1i (2.34 g, 8.6 mmol), triphenylphosphine (485 mg, 1.7 mmol), palladium acetate (200 mg, 0.86 mmol) and cesium acetate (2.5 g, 12.9 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residues were purified by TLC with elution system C to obtain the title compound, ('R /) - 5-nitro-1- (tetrahydrofuran-3 -M) -2- (4- (t-fluoromethyl) phenM) -1 H-indole 32c (300 mg, 9.4%) as a yellow solid.

MS m / z (ESI): 377.3 [M + 1]

Stage 3

(R) -5-Amino-1- (tetrahydrofuran-3-¡l) -2- (4- (trifluoromethyl) phenyl) -1 H-indole

(R) -5-nitro-1- (tetrahydrofuran-3-¡l) -2- (4- (trifluoromethyl) phenyl) -1 H-indole 32c (200 mg , 0.53 mmol) in a mixture of 10 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (20 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the title compound, (R) -5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) Phenyl) -1H-indole 32d (184 mg) as a yellow solid, which was used in the next step without further purification.

MS m / z (ESI): 347.0 [M + 1]

Stage 4

(R) -2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl ) phenyl) -1 H-indol-5-yl) nicotinamide

(R) -5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 32d (160 mg, 0.55 mmol), 2- (difluoromethyl acid) were added ) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinic 14b (190 mg, 0.55 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (158 mg, 0.83 mmol), 1-hydroxybenzotriazole (7 mg, 0.05 mmol) and N, N- diisopropylethylamine (142 mg, 1.1 mmol) in 10 ml of N, N-dimethylacetamide successively. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system A to obtain the title compound, (R) -2- (difluoromethyl) -5 - (( (2-fluoro-2-methylpropanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide 32 (100 mg, 29.4%) as a white solid.

MS m / z (ESI): 619.2 [M + 1]

1H NMR (400MHz, DMSO-da): 810.64 (s, 1H), 8.88 (s, 1H), 8.69 (t, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.91-7.89 (m, 2H), 7.78-7.76 (m, 2H), 7.71-7.69 (m, 1H), 7.40-7 , 39 (m, 1H), 7.31 (t, 1H), 6.65 (s, 1H), 5.13 (m, 1H), 4.48-4.46 (m, 2H), 4, 34-4.30 (m, 1H), 4.17-4.14 (m, 1H), 3.95-3.93 (m, 1H), 3.67-3.65 (m, 1H), 2.45-2.33 (m, 2H), 1.53-1.48 (d, 6H). Example 33

N- (2- (3-Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide

Stage 1

2- (3-Chlorophenyl) -1-methyl-5-nitro-1 H-indole

1-Methyl-5-nitro-1 H-indole 9a (2.0 g, 11.4 mmol) was dissolved in 20 ml of N, N-dimethylacetamide, and then added with 1-chloro-3-iodo-benzene 20a (2.7 g, 11.3 mmol), triphenylphosphine (620 mg, 2.2 mmol), palladium acetate (250 mg, 1.1 mmol) and cesium acetate (4.2 g, 22.0 mmol ) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residues were purified by TLC with elution system B to obtain the title compound, 2- (3-chlorophenyl) -1-methyl-5-nitro-1H-indole. 33a (300mg, 9.5%) as a light yellow solid.

MS m / z (ESI): 287.1 [M + 1]

Stage 2

2- (3-Chlorophenyl) -1-methyl-1 H-indole-5-amine

2- (3-chlorophenyl) -1-methyl-5-nitro-1H-indole 33a (300 mg, 1.05 mmol) was dissolved in a mixture of 20 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (30 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (3-chlorophenyl) -1-methyl-1H-indole-5-amine 33b (269 mg) as a yellow solid, the which was used in the next step without further purification. MS m / z (ESI): 257.1 [M + 1]

Stage 3

N- (2- (3-Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 2- (3-chlorophenyl) -1-methyl-1H-indole-5-amine 33b (269 mg, 1.05 mmol), 2- (difluoromethyl) -5 - (((2-fluoro-2- methylpropanoyl) amino) methyl) nicotinic 14b (305 mg, 1.05 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (302 mg, 1.58 mmol), 1-hydroxybenzotriazole (14 mg, 0 , 10 mmol) and N, N- diisopropylethylamine (271 mg, 2.1 mmol) in 10 ml of N, N-dimethylacetamide successively. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system A to obtain the title compound, N- (2- (3-chlorophenyl) -1-methyl -1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 33 (30 mg, 5.4% over two steps) in form of a white solid.

MS m / z (ESI): 529.1 [M + 1]

1H NMR (400 MHz, DMSO-d ⁶ ): ⁶ 10.60 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H), 8.06 (d, 2H), 7 , 69 (s, 1H), 7.56-7.51 (m, 4H), ^{7 April 5 to 7, 44} (m, 1H), 7.20 (s, 1H), 6.69 (s, 1H), 4.48-4.46 (m, 2H), 3.77 (s, 3H), 1.54 (s, 3H), 1.48 (s, 3H)

Example 34

2-Chloro-N- (2- (4-fluorophenyl) -1-methyl-1H-¡ndol-5-¡l) -5 - (((1- (tr¡fluorometh¡l) c¡ clopropanecarbonyl) amine) methyl) benzamide

Stage 1

2-Chloro-5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoic acid 5- (aminomethyl) -2-chlorobenzoic acid 34a (1.5 g, ^6.8 mmol, prepared according to the method disclosed in the patent application "WO2011048004") and N, N-diisopropylethylamine (2.63 g, 20.3 mmol) in 4 ml of dichloromethane and cooled to 0 ° C in an ice bath. 1- (Trifluoromethyl) cyclopropanecarbonyl chloride 34b (1.28 g, 7.5 mmol, prepared according to the method disclosed in patent application "WO2005023773") was added and the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound, 2-chloro-5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoic acid 34c (2.4 g) as of a light yellow oil, which was used in the next step without further purification.

MS m / z (ESI): 320.1 [M-1]

Stage 2

2-Chloro-5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoyl acid 2-chloro-5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoic chloride were dissolved 34c (200 mg, 0.62 mmol) and thionyl chloride (222 mg, 1.86 mmol) in 20 ml of dichloromethane and then added with a drop of A /, W-dimethylformamide. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound, 2-chloro-5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoyl chloride 34d (210 mg) as a light yellow oil, which was used in the next step without further purification.

Stage 3

2-Chloro-W- (2- (4-fluorophenyl) -1-methyl-1H-indol-5-yl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzamide 2- ( 4-fluorophenyl) -1-methyl-5-amino-1H-indole 11b (85 mg, 0.35 mmol) in 10 ml of dichloromethane, and then added with 2-chloro-5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoyl 34d (120 mg, 0.35 mmol) and A /, W-diisopropylethylamine (90 mg, 0.70 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-A / - (2- (4-fluorophenyl ) -1-methyl-1H-indol-5-yl) -5 - (((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzamide 34 (20 mg, 10.5%) as a yellow solid Sure.

MS m / z (ESI): 544.3 [M + 1]

1H NMR (400 MHz, DMSO-cfe): 810.37 (s, 1H), 8.47 (s, 1H), 8.06 (s, 1H), 7.66-7.64 (m, 2H) , 7.53-7.35 (m, 7H), 6.58 (s, 1H), 4.34-4.32 (m, 2H), 3.73 (s, 3H), 1.34-1 , 24 (m, 4H).

Example 35

N- (2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b1-pyridin-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) am No) met¡l) n¡cot¡nam¡da

Stage 1

6-Chloro-2-iodo-pyridin-3-amine

6-Chloropyridine-3-amine 35a (1 g, 7.78 mmol) was dissolved in 20 ml of N, N-dimethylformamide, and then added with N-iodosuccinimide (2.27 g, 10.11 mmol). The reaction solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 6-chloro-2-iodo-pyridin-3-amine 35b (1.37 g, 69.2%) as a brown solid.

Stage 2

6-Chloro-2- (2- (3-chlorophenyl) ethynyl) pyridin-3-amine

6-Chloro-2-iodo-pyridin-3-amine 35b (1.37 g, 5.38 mmol), 3-chlorophenylacetylene (882 mg, 6.46 mmol), bis (triphenylphosphine) palladium chloride (II ) (378 mg, 0.54 mmol), cuprous iodide (205 mg, 1.08 mmol) and N, N- diisopropylethylamine (1.39 g, 10.76 mmol) in 10 ml of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours at 100 ° C under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 6-chloro-2- ((3-chlorophenyl) ethynyl) pyridin-3-amine 35c (871 mg, 61 , 6%) as a brown solid.

Stage 3

5-Chloro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-6] pyridine

6-Chloro-2 - ((3-chlorophenyl) ethynyl) pyridin-3-amine 35c (871 mg, 3.32 mmol) and potassium ferc-butanolate (746 mg, 6.64 mmol) were dissolved in 20 ml of N , N-dimethylformamide. The resulting mixture was stirred for 16 hours at 70 ° C. The reaction mixture was concentrated under reduced pressure. The residues were added with 10 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 5-chloro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-b] pyridine 35d (1.17 g) as a yellow solid, which was used in the next step without further purification.

Stage 4

5-Chloro-2- (3-dorophenyl) -1-methyl-1H-pyrrolo [3,2- £)] pyridine

5-Doro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-6] pyridine 35d (1.17 g, 4.46 mmol) was dissolved in 15 ml of N, N-dimethylformamide, and then added with 60% sodium hydride (268 mg, 6.69 mmol). The reaction mixture was stirred for 30 min at room temperature. Iodomethane (761 mg, 5.36 mmol) was added and stirred continuously for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 5-chloro-2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-6 ] pyridine 35e (650 mg, 52.8%) as a yellow solid.

Stage 5

2- (3-chlorophenyl) -N- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [3,2-6] pyridin-5-amine 5-chloro-2- (3-chlorophenyl) -1 were dissolved -methyl-1H-pyrrolo [3.2-6] pyridine 35e (276 mg, 1.0 mmol), 4-methoxybenzylamine (172 mg, 1.25 mmol), tris (dibenzylideneacetone) dipalladium (92 mg, 0.1 mmol), (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (125 mg, 0.2 mmol), potassium phosphate (425 mg, 2 mmol) in 15 ml of 1,4- dioxane. The reaction mixture was stirred for 16 hours at 100 ° C under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (3-chlorophenyl) -N (4-methoxybenzyl) -1-methyl-1H-pyrrolo [3, 2-6] pyridin-5-amine 35f (221 mg, 58.5%) as a yellow solid. Stage 6

N- (2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [3,2-6] pyridin-5-yl) -2,2,2-trifluoroacetamide

2- (3-chlorophenyl) -N- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [3,2-6] pyridin-5-amine 35f (221 mg, 0.58 mmol) was dissolved in 5 ml of trifluoroacetic acid. The resulting mixture was stirred for 16 hours at 60 ° C. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound, N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-6] pyridin-5-yl) - 2,2,2-trifluoroacetamide 35h (207 mg) as a brown oil, which was used in the next step without further purification.

Stage 7

2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-amine

W- (2- (3-chlorophenyl) -1-methyl-1H-p¡rrolo [3.2- £)] p¡r¡d¡n-5-¡l) -2 were dissolved, 2,2-trifluoroacetamide 35h (207 mg, 0.58 mmol) and potassium carbonate (162 mg, 1.17 mmol) in 10 ml of ethanol. The reaction mixture was stirred for 1 hour at 80 ° C. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (3-chlorophenyl) -1-methyl -1H-pyrrolo [3,2-6] pyridin-5-amine 35j (30 mg, 20%) as a light yellow solid.

Stage 8

W- (2- (3-Chlorophenyl) -1-methyl-1H-p¡rrolo [3,2- £)] p¡r¡d¡n-5-¡l) -2- (d ¡Fluorometal) -5 - (((2-fluoro-2-methylpropanoyl) am¡no) methyl) nicot¡nam¡da

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) ncotinic acid 14b (34 mg, 0, 12 mmol) and 2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-amine 35j (30 mg, 0, 12 mmol) in 15 ml of A /, W-dimethylformamide and then added with triethylamine (47 mg, 0.46 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol) and 1-ethyl hydrochloride. (3-dimethylamnopropyl) carbodimide (34 mg, 0.17 mmol). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, W- ('2 - (' 3-chlorophenyl) -1-methyl-1H-p¡rrolo [3,2-6] p¡r¡d¡n-5-¡l) -2- (d¡fluoromet¡ l) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) n¡cot¡nam¡da 35 (3 mg, 4.8%) as a solid whitish in color.

MS m / z (ESI): 530.1 [M + 1]

1H NMR (400 MHz, CDCla): 88.63 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.54-7 , 43 (m, 4H), 7.31 (s, 1H), 6.93 (s, 1H), 6.42 (s, 1H), 4.43 (s, 2H), 3.83 (s, 3H), 1.64 (s, 3H), 1.59 (s, 3H).

Example 36

N- (2- (3-Chlorophenyl) -1-methyl-1H-p¡rrolo [2,3-c] p¡r¡d¡n-5-¡l) -2- (d¡ fluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amine) methyl) nicotamide

Stage 1

4-Iodo-6-nitro-pyridin-3-amine

5-amino-2-nitropyridine 36a (1 g, 7.2 mmol), potassium iodate (770 mg, 3.6 mmol) and potassium iodide (1.2 g, 7.2 mmol) in 30 ml of acid were added. sulfuric (2 N) successively. The reaction solution was stirred for 16 hours at 80 ° C and then cooled to room temperature. The reaction mixture was adjusted to pH 10 with a 2N aqueous sodium hydroxide solution. A quantity of solid precipitated and was filtered. The filter cake was washed with water, and dried to obtain the title compound, 4-iodo-6-nitro-pyridin-3-amine 36b (1.5 g, 79%) as a yellow solid. .

Stage 2

4 - ((3-Chlorophenyl) ethynyl) -6-nitro-pyridin-3-amine

4-Iodo-6-nitro-pyridin-3-amine 36b (1.5 g, 5.7 mmol), 3-chlorophenylacetylene (850 mg, 6.2 mmol), cuprous iodide (1.1 g, 5 , 7 mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (834 mg, 1.14 mmol) and triethylamine (1.6 ml, 11.4 mmol) in 20 ml of A /, W-dimethylformamide successively. The reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residues were purified by column chromatography on silica gel with elution system A to obtain the title compound 4 - ((3-chlorophenyl) ethynyl) -6-nitropyridin-3-amine 36c (1.5 g, 97%) as a yellow solid.

Stage 3

2- (3-Chlorophenyl) -5-nitro-1H-pyrrolo [2,3-c] pyridine

4 - ((3-chlorophenyl) ethynyl) -6-nitro-pyridin-3-amine 36c (200 mg, 0.73 mmol), potassium tert-butanolate (123 mg, 1.1 mmol) and 10 ml of A /, W-dimethylformamide in 50 ml flask. The resulting mixture was stirred for 16 hours at 60 ° C. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound, 2- (3-chlorophenyl) -5-nitro-1H-pyrrolo [2,3-c] pyridine 36d (300 mg) as a brown oil, which was used in the next step without further purification.

Stage 4

2- (3-Chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-c] pyridine

2- (3-chlorophenyl) -5-nitro-1H-pyrrolo [2,3-c] pyridine 36d (300 mg, 1.1 mmol), iodomethane (233 mg, 1.64 mmol), cesium carbonate were added (717 mg, 2.2 mmol) and 10 ml of W, W-dimethylformamide in 100 ml of flask. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (3-chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo (2,3-c ) pyridine 36e (50 mg, 15.8%) as a yellow solid.

Stage 5

2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-amine

2- (3-chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-c] pyridine 36e (50 mg, 0.17 mmol), Raney nickel (5 mg) and 10 ml of tetrahydrofuran in 50 ml flask. The reaction mixture was stirred for 2 hours at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound, 2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-amine 36f (40 mg, 88.9% ) as a light yellow solid.

Stage 6

W- (2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl ) amino) methyl) nicotinamide

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (45 mg, 0.16 mmol), 2- (3-chlorophenyl) -1- were dissolved methyl-1H-pyrrolo [2,3-c] pyridin-5-amine 36f (40 mg, 0.16 mmol), 1-hydroxybenzotriazole (2.2 mg, 0.016 mmol), 1-ethyl-3- hydrochloride ( 3-dimethylaminopropyl) carbodiimide (46 mg, 0.24 mmol) and A /, W-diisopropylethylamine (31 mg, 0.24 mmol) in W, A / -dimethylformamide. The reaction mixture was stirred for 2 hours at 70 ° C. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, W- (2- (3-chlorophenyl) -1-methyl -1H-pyrrolo [2,3-c] pyridin-5-yl) -2- (difluoro methyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 36 (20 mg, 23.5%) as a light yellow solid.

MS m / z (ESI): 530.1 [(M + 1])

1H NMR (400 MHz, DMSO-da): 811.15 (s, 1H), 8.82-8.80 (m, 1H), 8.67 (s, 1H), 8.07-8.05 ( m, 3H), 7.75 (s, 1H), 7.66 7.65 (m, 1H), 7.57-7.55 (m, 2H), 7.21 (s, 1H), 6, 72 (s, 1H), 4.46-4.44 (d, 2H), 3.83 (s, 3H), 1.53 (s, 3H), 1.48 (s, 3H). Example 37

N- (2- (3-Chlorophen¡l) -1-eth¡l-1H-p¡rrolo [3,2-¿) 1p¡r¡d¡n-5-¡l) -2- (d¡ Fluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) n¡cot¡nam¡da

Stage 1

2- (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cot¡noyl chloride was dissolved acid 2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín¡co 14 b (1, 5 g, 5.17 mmol) in 10 ml of dichloromethane, and then added with thylon chloride (1.2 ml, 15.5 mmol) and 2 drops of W, Wd¡met ¡Lformam¡da. The reaction solution was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound, 2- (di-fluoromethyl) -5 - (((2-fluoro-2-methyl -propano¡l) am¡no) methyl) n¡cot¡noyl 37a (1.6 g) in the form of a white solid, which was used in the next stage si¡ n additional purification.

Stage 2

5-Chloro-2- (3-chlorophenyl) -1-ethyl-1H-p¡rrolo [3,2- £)] p¡r¡d¡na

5-Chloro-2- (3-chlorophenyl) -1H-p¡rrolo [3.2-8jp¡r¡d¡na 35d (0.87 g, 3.32 mmol) was dissolved in 20 ml of A /, Wd¡methylformamide, and then added with 60% sodium hydroxide (0.2 g, 4.98 mmol). The reaction mixture was stirred for 30 min at room temperature, and then added with iodoethane (0.62 g, 3.98 mmol) and stirred continuously for another 2 hours at ambient temperature. The reaction mixture was added with 10 ml of water and concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system to obtain the title compound, 5-chloro-2- (3-chlorophenyl) - 1-Ethyl-1H-pyrrolo [3,2-bjpyrdina 37b (0.35 g, 36.3%) as a yellow oil.

Stage 3

(2- (3-Chlorophenil) -W- (d¡phen¡lmet¡len¡l) -1-et¡l-1H-p¡rrolo [3,2- £)] p¡r¡d¡ n-5-am¡na

5-doro-2- (3-dorofeml) -1-ethiMH-pyrrolo [3.2- £)] pina 37b (30 mg, 0.1 mmol), benzophenone imine (22 mg, 0 , 12 mmol), tris ^ ibenzylideneacetone ^ ipalladium (9.5 mg, 0.01 mmol), 4,5-b¡s (diphenylphosphine) -9,9-dimethylxanthene (12 mg, 0.021 mmol) and potassium phosphate (44 mg, 0.21 mmol) in 2 ml of 1,4-dioxane. The resulting mixture was stirred for 16 hours at 100 ° C under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residues were added with a little tetrahydrofuran and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, (2- (3-dorofen-l) -N- (d-phenyl-methyl) -1-ethyl-1H-p ¡Rrolo [3.2- £)] pi ^ d¡n-5-amine 37c (50 mg) as a gray solid, which was used in the next step without further purification.

Stage 4

2- (3-Chlorophenyl) -1-ethyl-1H-p¡rrolo [3,2- £)] p¡ ^ d¡n-5-amine

(2- (3-dorofen¡l) -N- (d¡phenylmet¡len¡l) -1-eth¡l-1H-p¡rrolo [3,2- £)] p¡ ^ d was dissolved N-5-amine 37c (50 mg, 0.12 mmol) in 10 ml of tetrahydrofuran, and then added with 4 ml of a 2M solution of hydrochloric acid. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then adjusted to pH> 7 with a saturated sodium bicarbonate solution. The mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the crude title compound 2- (3-dorofenl) -1-eti l-1H-p¡rrolo [3.2- £)] p¡ ^ d¡n-5-amine 37d (62 mg) as a yellow solid which was used in the next step without further purification .

Stage 5

W- (2- (3-Chlorophen¡l) -1-eth¡l-1H-p¡rrolo [3,2-b7p¡ ^ d¡n-5-¡l) -2- (d¡fluorometh¡l ) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinamide

2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cot¡noyl 37a (13, 5 mg, 0.044 mmol) in 10 ml of dichloromethane, and then added with triethylamine (94 mg, 0.088 mmol) and 2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2- 8] p¡ ^ d¡n-5-amine 37d (11.9 mg, 0.044 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, W- (2- (3-chlorophenyl) -1- et ¡L-1H-p¡rrolo [3,2-8] p¡ ^ d¡n-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2-met L-propanol) amine) methyl) nicotamide 37 (5 mg, 20.8%) as a white solid.

MS m / z (ESI): 544.1 [M + 1]

1H NMR (400 MHz, CDCla): 813.16 (s, 1H), 8.84-8.82 (d, 2H), 8.72-8.70 (d, 1H), 8.26-8, 24 (d, 1H), 7.57-7.52 (m, 3H), 7.43-7.42 (d, 1H), 7.36-7.31 (m, 2H), 6.81 ( s, 1H), 4.71-4.69 (d, 2H), 4.39-4.33 (m, 2H), 1.64 (s, 3H), 1.59 (s, 3H), 1 , 44 1.42 (m, 3H).

Example 38

2- (D¡fluoromethyl) -5 - ((2-methylpropane¡lam¡no) methyl) -W- (2- (4- (tr¡fluoromethyl) phen¡l) benzo [ d] oxazol-5-¡ln¡cot¡nam¡da

2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (120 mg, 0.44 mmol) was dissolved in 5 ml of W, W-dimethylformamide and then 2- (d¡fluoromethyl) -5 - ((2-methylpropanolamno) methyl) n¡cotin¡co acid 1f (100 mg, 0.37 mmol), hydrochloride of 1- (3-d¡methylamnopropyl) -3-ethylcarbod¡¡m¡da (140 mg, 0.74 mmol), 1-hydroxybenzotriazole (5 mg, 0.037 mmol) and triethylamine (200 pl, 1.47 pmol). The resulting mixture was heated to 70 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system A to obtain the title compound, 2- (d¡fluoromethyl) -5 - (( 2-methylpropanolamine) methyl) -A / - (2- (4- (t ^ fluoromethyl) phenyl) benzo [d] oxazol-5-i ^ nicotinamide 38 (60 mg 30.6%) as a white solid.

MS m / z (ESI): 533.2 [M + 1]

1H NMR (400 MHz, DMSO-cfe): 811.00 (s, 1H), 8.81 (s, 1H), 8.61 (t, 1H), 8.21-8.27 (m, 3H) , 8.10 (s, 1H), 7.83 (d, 1H), 7.72 (d, 3H), 7.22 (t, 1H), 4.44 (d, 2H), 2.49 (d, 1H), 1.06 (d, 6H).

Example 39

2- (D¡fluorometh¡l) -5 - ((2-methylpropane¡lam¡no) methyl) -N- (2- (4- (tr¡fluorometh¡l) phen¡l) benzofuran- 5-¡l) n¡cot¡nam¡da

5-Amino-2- (4- (trifluoromethyl) phenyl) benzofuran 29d (70 mg, 0.25 mmol), 2- (di-fluoromethyl) acid were added -5 - ((2-methylpropanolamno) methyl) n¡cotín¡co 1f (69 mg, 0.25 mmol), 1- (3-d¡meth¡lam¡ hydrochloride nonprop¡l) -3-ethylcarbod¡¡m¡da (97 mg, 0.51 mmol), 1-hydroxybenzotr¡azole (3 mg, 0.025 mmol) and tr¡et¡lam¡na ( 140 µl, 0.80 pmol) in 5 ml of N, N- dimethylformamide successively. The resulting mixture was heated to 70 ° C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the Title compound, 2- (d¡fluoromethyl) -5 - ((2-methylpropano¡lamno) methyl) -N- (2- (4- (tr¡fluoromethyl) phen¡ l) benzofuran-5-¡l) n¡cotinamide 39 (70 mg, 52.2%) as an off-white solid. MS m / z (ESI): 532.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.81 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 8.15 (d, 2H), 8.04 (s, 1H), 7.89 (d, 2H), 7.73 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H) , 7.19 (s, 1H), 4.44 (d, 2H), 2.47 (d, 1H), 1.06 (d, 6H).

Example 40

2- (D¡fluorometh¡l) -5 - ((2-methylpropane¡lam¡no) methyl) -N- (2- (4- (tr¡fluorometh¡l) phen¡l) ¡so ¡Ndol¡n-5-¡l) n¡cot¡nam¡da

2- (4- (trifluoromethyl) phenil) sondolin-5-amine 25d (10 mg, 0.036 mmol) and acid 2- (d ¡Fluoromethyl) -5 - ((2-methylpropano¡lam¡no) methyl) n¡cotín¡co 1f (10 mg, 0.036 mmol) in 5 ml of N, Nd¡met¡lformam¡da , and then 1- (3-d¡methylamnopropyl) -3-ethylcarbod¡¡m¡da (11 mg, 0.054 mmol) and 1-h¡ droxybenzotrazole (5 mg, 0.036 mmol). The resulting mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, 2- (d¡fluoromethyl) -5 - ((2-methylpropane¡lam¡no) methyl) -N- (2- (4- (tr¡fluoromethyl) phen¡l) ¡so Ndolin-5-yl) nicotinamide 40 (10 mg, 52.6%) as a white solid.

MS m / z (ESI): 533.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.62 (s, 1H), 8.66 (s, 1H), 8.44 (d, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.88-7.85 (m, 4H), 7.54 (d, 1H), 7.47 (d, 1H), 7.42 (t, 1H), 4.60 ( s, 4H), 4.41 (d, 2H), 3.18-3.17 (m, 1H), 1.05 (s, 6H)

Example 41

2-Chloro-5 - (((1-meth¡lcyclopropanecarbon¡l) am¡no) methyl) -A / - (2- (4- (th¡¡fluorometh¡l) phen¡l) benzo [d] oxazol-5-l) benzamide

Stage 1

2-chloro-5 acid - (((1-methylcyclopropanecarbon¡l) amno) methyl) benzo¡co

5- (amnomethyl) -2-chloro-benzoic acid 34a (1.5 g, 6.8 mmol, prepared according to the d¡vulgado method in the sun was dissolved Patent number "WO2011048004") and tritlamine (3.2 ml, 23.2 mmol) in 15 ml of tetrahydrofuran and then cooled to 0 ° C in a bath of do it. A solution of 1-methylcyclopropanecarbonyl chloride 41a (890 mg, 7.47 mmol, prepared according to the method described in "Journal of Medical Chem¡stry, 2014, 57 (22), 9323 9342 ") in 5 ml of tetrahydrofuran was added to the mixture above dropwise. The reaction mixture was warmed to room temperature and then stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound, 2-chloro-5 acid - (((1-methylcyclopropanecarbonyl) amine) methyl) benzo¡co 41b (4.78 g,) in the form of a white solid, which was used in the next stage without purification ad¡ conal.

MS m / z (ESI): 266.1 [M-1]

Stage 2

2-Chloro-5 - (((1-methylcyclopropanecarbon¡l) am¡no) methyl) benzoyl chloride

2-Aloro-5 - (((1-methylcyclopropanecarbonl) amino) methyl) benzoic acid 41b (200 mg, 0.75 mmol) was dissolved in 10 ml of dichloromethane and then added with thonyl chloride (0.2 ml, 2.75 mmol). The reaction solution was stirred for 15 min at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the title compound, 2-chloro-5 - (((1-methylcyclopropanecarbonyl) amine) methyl chloride. ) crude benzoyl 41c (220 mg) in the form of a yellow oil, which was used in the next stage without additional purification.

Stage 3

2-Chloro-5 - (((1-methylcyclopropanecarbon¡l) am¡no) methyl) -A / - (2- (4- (tr¡fluoromethyl) phen¡l) benzo [ d] oxazol-5-¡l) benzamide 2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-6-amine 22c (90 mg, 0.33 mmol) and tritlamine (90 pl, 0.65 pmol) in 5 ml of tetrahydrofuran, and then added dropwise with a chloride solution of 2-chloro-5 - (((1-methylcidopropanecarbonyl) amino) methyl) benzoyl 41c (220 mg, 0.72 mmol) in 5 ml of tetrahydrofuran. The reaction mixture was stirred for 30 min. The reaction mixture was filtered and concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2-chloro-5 - (((1-methylcyclopropanecarbonyl) amino) methyl) -W- (2- (4 - (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide 41 (30 mg, 17.4% over two steps) as a yellow solid.

MS m / z (ESI): 528.3 [M + 1]

1H NMR (400MHz, DMSO-da): 810.78 (s, 1H), 8.42 (d, 2H), 8.33 (s, 1H), 8.23 (t, 1H), 8.01 (d, 2H), 7.84 (d, 1H), 7.72 (d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.39 (d, 1H) , 4.31 (d, 2H), 1.30 (s, 3H), 0.97 (d, 2H), 0.54 (d, 2H).

Example 42

W- (2- (4-Chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinamide

Stage 1

Ethyl 2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinate was dissolved ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinate hydrochloride (1.8 g, 5.94 mmol) in 25 ml of W, A / -dimethylformamide, and then added with 1-methylcyclopropane-1-carboxylic acid 42a (594 mg, 5.94 mmol), 1- (3-dimethylaminopropyl) -3-ethyl hydrochloride -carbodiimide (2.28 g, 11.9 mmol), 1-hydroxybenzotriazole (80 mg, 0.59 mmol) and triethylamine (3.3 ml, 23.8 mmol) successively. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residues were added with 50 ml of water and extracted with ethyl acetate (25 mlx3). The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by column chromatography on silica gel with elution system C to obtain the title compound, 2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) - Ethyl amino) methyl) nicotinate 42b (1.2 g, 64.9%) as a light yellow oil.

MS m / z (ESI): 313.2 (M + 1)

Stage 2

2- (Difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinic acid

Ethyl 2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinate 42b (1.2 g, 3.85 mmol) was dissolved in 30 ml the mixture of 1,4-dioxane and water (V: V = 2: 1) and then added with lithium hydroxide hydrate (400 mg, 9.62 mmol). The reaction mixture was stirred for 16 hours. The 1,4-dioxane was removed under reduced pressure and the residues were adjusted to pH 4-5 by 6M hydrochloric acid. A quantity of solid precipitated and was added with 30 ml of ethyl acetate and filtered. The filter cake was collected and the filtrate was layered. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residues were combined with the filter cake above to obtain the title compound, 2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) pyridine-3-carboxylic acid. 42c (1.0g, 91.7%) as a white solid. MS m / z (ESI): 285.1 [M + 1].

Stage 3

W- (2- (4-Chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinamide 2- ( difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinic 42c (52 mg, 0.19 mmol), 1-ethyl-2- (4-chlorophenyl) -5-amino-1H-indole 10c ( 50 mg, 0.19 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (2.5 mg, 18.5 pmol), and triethylamine (100 pl, 0.74 mmol) in 5 ml of A /, W-dimethylformamide. The reaction mixture was heated to 70 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, N- (2- (4-chlorophenyl) -1-ethyl-1H-indol-5-yl) -2 - (Difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinamide 42 (40 mg, 40.4%) as a yellow solid.

MS m / z (ESI): 538.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.62 (s, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 8.04 (d, 2H), 7.55 -7.69 (m, 3H), 7.44 (d, 2H), 7.19 (t, 1H), 6.60 (s, 1H), 4.43 (d, 2H), 4.22 ( d, 2H), 1.32 (s, 3H), 1.20 (t, 3H), 1.00 (s, 3H), 0.56 (s, 2H).

Example 43

2- (Difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) -W- (2- (4- (thiifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide

2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (50 mg, 0.18 mmol) was dissolved in 5 ml of A /, W-dimethylformamide, and then added with acid 2- (Difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) nicotinic 42c (51 mg, 0.18 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75 mg, 0, 39 mmol), 1-hydroxybenzotriazole (2.4 mg, 0.018 mmol) and triethylamine (0.1 ml, 720 pmol). The reaction mixture was heated to 70 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((1-methylcyclopropanecarbonyl) amino) methyl) -A / - (2 - (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 43 (20 mg, 20.4%) as a yellow solid.

MS m / z (ESI): 545.3 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.95 (s, 1H), 8.70 (d, 1H), 8.43 (d, 2H), 8.30 (t, 2H), 8.03 (d, 3H), 7.87 (d, 1H), 7.72 (d, 1H), 7.19 (t, 1H), 4.43 (d, 2H), 1.31 (s, 3H) , 0.99 (d, 2H), 0.56 (d, 2H).

Example 44

W- (2- (4-Chlorophenyl) -1-methyl-1H-pyrrolo (2,3-d) pyridin-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl ) amino) methyl) nicotinamide

Stage 1

3 - ((4-Chlorophenyl) ethynyl) -5-nitro-pyridin-2-amine

2-amino-3-iodo-5-nitro-pyridine 44b (300 mg, 1.13 mmol), 4-chlorophenylacetylene 44a (325 mg, 2.38 mmol), bis (triphenylphosphine) palladium (II) chloride were added (40 mg, 56.5 µmol), cuprous iodide (11 mg, 56.5 µmol) and triethylamine (1.6 ml, 11.3 mmol) added in 20 ml of A /, W-dimethylformamide successively. The reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was added with 100 ml of ethyl acetate and washed with water (50 mlx2). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 3 - ((4-chlorophenyl) ethynyl) -5-nitropyridin-2-amine 44c (250 mg, 80, 9%) as a yellow solid. MS m / z (ESI): 272.0 [M-1]

Stage 2

2- (4-Chlorophenyl) -5-nitro-1H-pyrrolo (2,3- £)) pyridine

3- (4-chlorophenyl) ethynyl) -5-nitro-pyridin-2-amine 44c (160 mg, 0.58 mmol) and potassium tert-butanolate (746 mg, 6.64 mmol) were dissolved in 10 ml of A /, W-dimethylformamide. The reaction mixture was heated to 70 ° C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residues were mixed with 50 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-chlorophenyl) -5-nitro-1H-pyrrolo (2,3-6) pyridine 44d (160 mg) as a solid of yellow color, which was used in the next step without further purification.

MS m / z (ESI): 273.0 [M-1]

Stage 3

2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3- £)] pyridine

2- (4-chlorophenyl) -5-nitro-1H-pyrrolo [2,3-6] pyridine 44d (160 mg, 0.58 mmol) was dissolved in 5 ml W, A / -dimethylformamide and then added with carbonate of cesium (380 mg, 1.17 mmol) and iodomethane (73 µl, 1.17 mmol. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residues were purified by layer chromatography fine (TLC) with a C elution system to obtain the title compound, 2- (4-chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-6] pyridine 44e (30 mg, 17 , 9% over two steps) as a yellow solid MS m / z (ESI): 290.0 [M + 1]

E cover 4

2- (4-Chlorophenyl) -1-methyl-1H-p¡rrolo [2,3- £)] p¡r¡d¡n-5-amine

2- (4-chlorophenyl) -1-methyl-5-nitro-1H-p¡rrolo [2,3- £)] p¡r¡d¡na 44e ( 50 mg, 0.17 mmol) in a mixture of 10 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (30 mg). The reaction mixture was stirred for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered with celatom, and the filter was concentrated under reduced pressure to obtain the crude title compound, 2- (4-chlorophenyl) -1-methane. l-1H-p¡rrolo [2,3-8] p¡r¡d¡n-5-amine 44f (45 mg) as a light yellow solid, which was used in the next stage without additional purification.

MS m / z (ESI): 259.1 [M + 1]

Stage 5

N- (2- (4-Chlorophenyl) -1-methyl-1H-p¡rrolo [2,3- £)] p¡r¡d¡n-5-¡l) -2- (d ¡Fluorometh¡l) -5 - (((2-fluoro-2-methylpropano¡l) am¡no) methyl) n¡cot¡nam¡da

2- (4-chlorophenyl) -1-methyl-1H-p¡rrolo [2,3- £)] p¡r¡d¡n-5-amine 44f (50 mg , 0.17 mmol), 2- (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín acid ¡Co 14b (50 mg, 0.17 mmol), 1-ethyl- (3-d¡meth¡lam¡nopropyl) -3carbod¡¡m¡hydrate (67 mg, 0.35 mmol) and 1-hydroxybenzotrazole (2.3 mg, 17.4 pmol) in 5 ml of N, N- dimethylformamide successively. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, N- (2- (4-chlorophenyl) -1-methyl-1H-p¡rrolo [2,3-8] p¡r¡d¡n-5-¡l) -2 - (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cot¡nam¡da 44 (3 mg, 3, 3%) in the form of a yellow solid.

MS m / z (ESI): 531.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.86 (s, 1H), 8.71 (s, 1H), 8.51 (t, 1H), 8.20-8.27 (m, 2H) , 8.05 (s, 2H), 7.82 (d, 1H), 7.71 (d, 2H), 7.19 (t, 1H), 6.55 (s, 1H), 4.47 ( d, 2H), 3.83 (s, 3H), 1.54 (s, 3H), 1.48 (s, 3H).

Example 45

N- (2- (4-Chlorophenyl) benzo [d] oxazol-5-¡l) -2- (d¡fluoromethyl) -5 - ((2-methylpropano¡lam¡no) methyl l) n¡cot¡nam¡da

Stage 1

2- (4-Chlorophenyl) benzo [d] oxazol-5-amine

2,4-diaminophenol (800 mg, 6.45 mmol) and 4-chlorobenzoic acid (1.1 g, 7.1 mmol) were dissolved in 10 ml of acid. do pol¡fosfór¡co. The reaction mixture was heated to 95 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature and poured into 50 ml of ice-cold water and adjusted to pH 7 with the dropwise addition of a sodium hydroxide solution. The mixture was extracted with ethyl acetate (30 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the compound of titer, 2- (4-chlorophenyl) benzo [d] oxazol-5-amine 45a (90 mg, 5.7%) as a gray solid.

MS m / z (ESI): 259.1 [M + 1]

Stage 2

N- (2- (4-Chlorophenyl) benzo [d] oxazol-5-¡l) -2- (d¡fluoromethyl) -5 - ((2-methylpropano¡lam¡no) methyl l) n¡cot¡nam¡da

2- (4-chlorophenyl) benzo [d] oxazol-5-amine 45a (80 mg, 0.33 mmol) and acid 2- (d¡fluoromethyl) - were dissolved 5 - ((2-methylpropanolamno) methyl) n¡cotín¡co if (81 mg, 0.30 mmol) in 5 ml of N, Nd¡met¡lformamide, and then added with 1- (3-dimethylamnopropyl) -3-ethyl-carbodiumhydrate (67 mg, 0.35 mmol), 1-hydrox Benzotrazole 4 mg, 0.030 mmol) and tri-ethylamine (0.16 ml, 1.19 pmol). The reaction mixture was heated to 70 ° C and stirred for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the title compound, N - ('2 - (' 4-chlorophenyl ) benzo [d] oxazol-5-¡l) -2- (d¡fluoromethyl) -5 - ((2-methylpropane¡lam¡no) methyl) n¡cot¡nam¡da 45 ( 6 mg, 4.1%) as a brown solid.

MS m / z (ESI): 499.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.96 (s, 1H), 8.70 (s, 1H), 8.51 (t, 1H), 8.20-8.27 (m, 3H) , 8.05 (s, 1H), 7.82 (d, 1H), 7.71 (d, 3H), 7.20 (t, 1H), 4.44 (d, 2H), 2.49 ( d, 1H), 1.06 (d, 6H).

Example 46

(S) -N- (2- (4-Chlorophenyl) -1 - (- tetrahydrofuran-3-¡l) -1H-¡ndol-5-¡l) -2- (d¡fluorometh¡l ) -5 - (((2-fluoro-2-methylpropano¡l) am¡no) methyl) n¡cot¡nam¡da

Stage 1

(S) -2- (4-chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-¡l) -1H-andol

(S) -5-nitro-1- (tetrahydrofuran-3-¡l) -1H-indole 31b (2.0 g, 8.6 mmol) was dissolved in 15 ml of N , Nd¡metalacetamide, and then added with 4-chloro-iodo-benzene 46a (2.3 g, 9.5 mmol), triphenylphosphine (450 mg, 1.7 mmol), palladium acetate (97 mg, 0.4 mmol) and cesium acetate (4.1 g, 21.6 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an atmosphere of argon. The reaction solution was cooled to room temperature and added with 200 ml of water, then extracted with ethyl acetate (200 ml × 1). The organic phase was dried anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound, (S) -2- (4-chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-¡ l) -1H-indole 46b (100 mg, 3.4%) as a yellow solid.

MS m / z (ESI): 343.1 [M + 1]

Stage 2

(S) -2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-¡l) -1H-andol-5-amine

(S) -2- (4-chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-¡l) -1H-andol 46b (70 mg, 0, 20 mmol) in 10 ml of mixture of tetrahydrofuran and methanol (V: V = 1: 1), and then added with Raney nickel (20 mg). The reaction mixture was stirred for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, (S) -2- (4-chlorophenyl) -1- (tetrahydrofuran-3-¡l) -1H-andol 5-amine 46c (64 mg) as a yellow solid, which it was used in the next step without further purification.

MS m / z (ESI): 313.1 [M + 1]

Stage 3

(S) -W- (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2 -methylpropanoyl) amino) methyl) nicotinamide

(S) -2- (4-chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-amine 46c (64 mg, 0.21 mmol), 2- (difluoromethyl) -5 acid were added - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic 14b (100 mg, 0.35 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (63 mg, 0.69 mmol ), 1-hydroxybenzotriazole (4.7 mg, 0.03 mmol) and triethylamine (0.2 ml, 1.38 mmol) in 5 ml of W, A / -dimethylformamide successively. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, (S) -A / - (2- (4-chlorophenyl ) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 46 (30 mg, 14.9%) as a yellow solid.

MS m / z (ESI): 586.2 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.61 (s, 1H), 8.86 (a, 1H), 8.69 (d, 1H), 8.09 (d, 1H), 8.01 (s, 1H), 7.67 (d, 2H), 7.61 (d, 2H), 7.55 (d, 1H), 7.36 (d, 1H), 7.18 (t, 1H) , 6.55 (s, 1H), 5.11 (a, 1H), 4.47 (d, 2H), 4.32 (t, 1H), 4.13 (dd, 1H), 3.91 ( t, 1H), 3.66 (d, 1H), 2.36-2.45 (m, 1H), 2.26-2.32 (m, 1H), 1.54 (s, 3H), 1 , 48 (s, 3H).

Example 47

(R) -A / - (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5 - (((2-fluoro- 2-methylpropanoyl) amino) methyl) nicotinamide

Stage 1

(R) -2- (4-Chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole

(R) -5-Nitro-1- (tetrahydrofuran-3-yl) -1H-indole 32b (2.0 g, 8.6 mmol) was dissolved in 30 ml of N, N-dimethylacetamide, and then added with 4-chloro-iodo-benzene 46a (2.1 g, 8.6 mmol), triphenylphosphine (508 mg, 1.8 mmol), palladium acetate (200 mg, 0.86 mmol) and cesium acetate (3, 5 g, 18 mmol) successively. The reaction mixture was heated to 140 ° C and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system B to obtain the title compound, (R) -2- (4-chlorophenyl) -5- Nitro-1- (tetrahydrofuran-3-yl) -1 H-indole 47a (280 mg, 9.0%) as a yellow solid. MS m / z (ESI): 343.9 [M + 1]

Stage 2

(R) -2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-¡l) -1H-andol-5-amine

(R) -2- (4-chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-¡l) -1H-andol 47a (280 mg, 0.82 mmol) was dissolved in 20 ml and then added with Raney nickel (28 mg). The reaction mixture was stirred for 3 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the title compound, (R) -2- (4-chlorophenyl) -1- (tetrahydrofuran-3-¡l) -1H¡ndol-5-amine 47b in crude (230 mg) as a yellow solid, which was used in the next step without further purification.

MS m / z (ESI): 313.1 [M + 1]

Stage 3

(R) -N- (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-andol-5-¡l) -2- (d¡fluoromethyl) - 5 - (((2-fluoro-2-met¡lpropano¡l) am¡no) methyl) n¡cot¡nam¡da

(R) -2- (4-chlorophenyl) -1- (tetrahydrofuran-3-¡l) -1H-andol-5-amine 46c (230 mg, 0.74 mmol), acid 2 - (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín¡co 14b (213 mg, 0.74 mmol ), 1-ethyl- (3-dimethylamnopropyl) carbodide hydrochloride (211 mg, 1.1 mmol), 1-hydroxybenzotriazole (10 mg, 0.074 mmol) and N, N- diisopropylethylamine (200 mg, 1.47 mmol) in 5 ml of N, N-dimethylformamide successively. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, (R) -N- (2- (4-chlorophene) l) -1- (tetrahydrofuran-3-¡l) -1H-¡ndol-5-¡l) -2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methylpropanoyl) amino) methyl) nicotamide 47 (100 mg, 23.3%) as a white solid.

MS m / z (ESI): 586.3 [M + 1]

1H NMR (400MHz, DMSO-da): 810.61 (s, 1H), 8.86 (t, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.76 (d, 1H), 7.61 (d, 2H), 7.55 (d, 2H), 7.38 (d, 1H), 7.18 (t, 1H) , 6.55 (s, 1H), 5.10 (a, 1H), 4.47 (d, 2H), 4.31 (t, 1H), 4.13 (d, 1H), 3.92 ( t, 1H), 3.65 (dd, 1H), 2.40 (d, 1H), 2.32 (d, 1H), 1.54 (s, 3H), 1.48 (s, 3H).

Example 48

2- (D¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -N- (2- (3- (tri-fluoromethyl) ) fen¡l) benzofuran-5-¡l) n¡cot¡nam¡da

Stage 1

5-Nitro-2- (3- (trifluoromethyl) phenyl) benzofuran

3- (Trifluoromethyl) (pinacolboril) benzene 48a (143 mg, 0.53 mmol) and 2-bromo-5-nitro-benzofuran 48b (85 mg, 0.35 mmol, prepared according to the method disclosed in "Organic & Biomolecular Chemistry, 2013, 11 (24), 4095-4101") a mixture of 6 ml of 1,4-dioxane and water (V: V = 5: 1), and then added with ( 1,1'-bis (diphenylphosphino) ferrocene) -d¡chloropallad¡o (II) (26 mg, 0.036 mmol) and sodium carbonate (75 mg, 0.71 mmol). The reaction mixture was heated to 100 ° C and stirred for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residues were purified by thin layer chromatography (TLC) with a C elution system to obtain the title compound, 5-nitro-2- (3- (trifluoromethyl) phenyl) benzofuran 48c (64 mg, 64 , 0%) as a yellow solid.

Stage 2

2- (3- (Trifluoromethyl) phenyl) benzofuran-5-amine

5-Nitro-2- (3- (trifluoromethyl) phenyl) benzofuran 48c (64 mg, 0.21 mmol) was dissolved in a mixture of 10 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (20 mg). The reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the title compound, 2- (3- (trifluoromethyl) phenyl) benzofuran-5-amine 48d (45 mg, 77.6%) as a yellow oil.

Stage 3

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide 2- (3- (trifluoromethyl) phenyl) benzofuran-5-amine 48d (23 mg, 0.083 mmol), 2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (24 mg, 0.083 mmol), 1-Ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (32 mg, 0.17 mmol) and 1-hydroxybenzotriazole (11.2 mg, 0.083 mmol) in 3 ml A /, W -dimethylacetamide successively. The reaction mixture was heated to 40 ° C. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro -2-methylpropanoyl) amino) methyl) -A / - (2- (3- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide 48 (10 mg, 21.7%) as a light yellow solid .

MS m / z (ESI): 550.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 88.68 (s, 1H), 8.15-8.11 (d, 2H), 8.04-8.00 (d, 3H), 7.61- 7.52 (m, 3H), 7.39-7.38 (d, 1H), 7.15-6.85 (m, 3H), 4.58-4.57 (d, 2H), 1, 64 (s, 3H), 1.58 (s, 3H).

Example 49

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) isoindolin-5-yl) nicotinamide

Stage 1

6-Nitro-2- (3- (trifluoromethyl) phenyl) isoindolin-1-one

3- (trifluoromethyl) aniline 49a (773 mg, 4.8 mmol) was dissolved in 15 ml of acetic acid and then added with methyl 2- (bromomethyl) -5-nitro-benzoate 25a (1.1 g, 4 , 0 mmol). The reaction mixture was heated to 110 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature. A quantity of solid precipitated and was filtered. The filter cake was dried to obtain the title compound, 6-nitro-2- (3- (trifluoromethyl) phenyl) isoindolin-1-one 49b (300 mg, 23.2%) as a white solid.

MS m / z (ESI): 323.0 [M + 1]

Stage 2

6-Amino-2- (3- (trifluoromethyl) phenyl) isoindolin-1-one

6-Nitro-2- (3- (trifluoromethyl) phenyl) isoindolin-1-one 49b (300 mg, 0.93 mmol) was dissolved in a mixture of 40 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (30 mg). The reaction mixture was stirred for 16 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom and the filter cake was washed with 30 ml of ethyl acetate. The filtrate was combined and concentrated under reduced pressure to obtain the crude title compound, 6-amino-2- (3- (trifluoromethyl) -phenyl) isoindolin-1-one 49c (272 mg) as a solid of black color, which was used in the next step without further purification.

MS m / z (ESI): 293.2 [M + 1]

Stage 3

2- (3- (Trifluoromethyl) phenyl) isoindolin-5-amine

Lithium aluminum hydride (70 mg, 1.86 mmol) in 10 ml of tetrahydrofuran was added, and then cooled in an ice bath. The solution was slowly added dropwise with 10 ml of solution of 6-amino-2- (3- (trifluoromethyl) phenyl) isoindolin-1-one 49c (271 mg, 0.93 mmol) in tetrahydrofuran. The ice bath was removed and the reaction mixture was heated to 65 ° C and then stirred for 1 hour. The reaction mixture was added with 2 ml of 1M sodium hydroxide solution and filtered. The filter cake was washed with 20 ml of ethyl acetate. The filtrate was combined and concentrated under reduced pressure to obtain the crude title compound, 2- (3- (trifluoromethyl) phenyl) isoindolin-5-amine 49d (258 mg) as a black solid, which it was used in the next step without further purification. MS m / z (ESI): 279.1 [M + 1]

Stage 4

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) isoindolin-5-yl) nicotinamide 2- (3- (trifluoromethyl) phenyl) isoindolin-5-amine 49d (258 mg, 0.93 mmol), 2- (difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl acid) nicotinic 14b (270 mg, 0.93 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (357 mg, 01.86 mmol), 1-hydroxybenzotriazole (13 mg, 0.093 mmol) and triethylamine (375 mg , 3.72 mmol) in 5 ml of W, A / -dimethylacetamide successively. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro -2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) isoindolin-5-yl) nicotinamide 49 (25 mg, 4.9% over three steps) as a solid yellow.

MS m / z (ESI): 551.2 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.79 (s, 1H), 8.87 (br, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H), 7.47 (t, 1H), 7.41 (d, 1H), 7.16 (s, 1H), 6.97 (t, 2H) , 6.89 (s, 1H), 4.68 (d, 3H), 4.47 (d, 2H), 4.39-4.44 (m, 1H), 1.54 (s, 3H), 1.48 (s, 3H).

Example 50

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide

Stage 1

5-Nitro-2- (3- (tnfluoromethyl) feml) -2H-ndazole

2- (3- (trifluoromethyl) phenyl) indazole 50a (28 mg, 0.11 mmol) and sodium nitrate (14.5 mg, 0.17 mmol) were added in 1 ml of concentrated sulfuric acid. The reaction mixture was heated to 70 ° C and stirred for 0.5 hours. The reaction mixture was cooled to room temperature and then poured into 20 ml of saturated sodium carbonate solution, then extracted with ethyl acetate (30 mlx3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound, 5-nitro-2- (3- (trifluoromethyl) -feml) -2H-indazole 50b (30 mg, 91.5%) as a colored solid yellow.

MS m / z (ESI): 308.1 [M + 1]

Stage 2

2- (3- (T ^ fluoromethyl) phenyl) -2H-ndazol-5-amine

5-nitro-2- (3- (t-fluoromethyl) phenyl) -2H-ndazole 50b (30 mg, 0.098 mmol) was dissolved in a mixture of 10 ml of tetrahydrofuran and methanol (V: V = 1: 1) and then added with Raney nickel (10 mg). The reaction mixture was stirred for 1 hour under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (3- (t-fluoromethyl) phenyl) -2H-ndazol-5-amine 50c (25 mg, 92, 6%) as a yellow solid.

MS m / z (ESI): 278.1 [M + 1]

Stage 3

2- (D¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -W- (2- (3- (t ^ fluoromet ¡L) phen¡l) -2H-indazol-5-¡l) n¡cot¡nam¡da 2- (3- (t ^ fluoromethyl) phen¡l) -2H-indazol-5 were added -amine 50c (25 mg, 0.090 mmol), 2- (difluoromethyl) -5 - (((2-fluoro ^ -metN-propanoi ^ amino ^ ethi ^ mcotmic acid 14b (26 mg, 0.090 mmol), hydrochloride 1-ethyl- (3-dimethylaminopropylcarbodiimide (35 mg, 0.18 mmol), 1-hydroxybenzotriazole (1.2 mg, 9.02 pmol) and triethylamine (50 µl, 0.36 mmol) in 5 ml AA -dimethylacetamide successively. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro-2-methylpropanol) amino) methyl) -W- (2- (3- (trifluoromethyl) phenil ) Indazol-5-II) Nicotamida 50 (14 mg, 28.6%) as a yellow solid.

MS m / z (ESI): 550.2 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.80 (s, 1H), 9.30 (s, 1H), 8.89 (br, 1H), 8.70 (s, 1H), 8.44 (d, 2H), 8.37 (s, 1H), 7.85 (s, 1H), 7.76-7.81 (m, 2H), 7.77 (d, 1H), 7.48 ( d, 1H), 7.20 (t, 1H), 4.47 (d, 2H), 1.54 (s, 3H), 1.48 (s, 3H).

Example 51

W- (2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] ¡m¡dazol-5-¡l) -2- (d¡fluoromethyl) -5 - (( 2-met¡lpropane¡lam¡no) methyl) n¡cot¡nam¡da

Stage 1

2- (4-Chlorophenyl) -1-ethyl-5-nitro-benzo [d] imidazole

2- (4-chlorophenyl) -5-nitro-1H-benzo [d] imidazole 51e (600 mg, 2.29 mmol, prepared according to the method disclosed in "Monatshefte Fuer Chemie, 2009, 140 (5) , 547-552 ") in 40 ml of W, A / -dimethylformamide and then added with sodium hydride (87 mg, 2.29 mmol), The reaction mixture was stirred for 0.5 hour and then added with iodoethane (512mg, 3.28mmol) and stirred continuously for another 3 hours. After completion of the reaction, the reaction mixture was quenched with 30 ml of water and extracted with ethyl acetate (30 mlx3), washed with a saturated solution of sodium chloride (30 mlx2), dried over anhydrous sodium sulfate, and leaked. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (4-chlorophenyl) -1-ethyl-5-nitro- benzo [d] imidazole 51f (540 mg, 82.0%) as a yellow paste.

MS m / z (ESI): 302.1 [M + 1]

Stage 2

2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-amine

2- (4-chlorophenyl) -1-ethyl-5-nitro-1H-benzo [d] imidazole 51f (150 mg, 0.49 mmol) was dissolved in 10 ml of methanol and then added with Raney nickel ( 15 mg). The reaction mixture was stirred for 14 hours at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-chlorophenyl) -1-ethyl-1H-benzo [d] imidazole-5-amine 51 g (100 mg) as a paste. brownish in color, which was used in the next step without further purification. MS m / z (ESI): 272.2 [M + 1] Step 3

W- (2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-yl) -2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinamide 2- ( 4-chlorophenyl) -1-ethyl-benzo [d] imidazol-5-amine 51 g (50 mg, 0.87 mmol), 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid 1f ( 80 mg, 0.87 mmol), 1-hydroxybenzotriazole (25 mg, 0.87 pmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (70 mg, 0.367 mmol) in 3 ml of W, A / -dimethylacetamide successively. The reaction mixture was stirred for 3.5 hours at 40 ° C. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, W- (2- (4-chlorophenyl) -1-ethyl -1H-benzo [d] imidazol-5-yl) -2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) -nicotinamide 51 (40 mg, 40%) as a light yellow solid.

MS m / z (ESI): 526.7 [M + 1]

1H NMR (400MHz, DMSO-da): 810.50 (br, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 8.13 (d, 2H), 8.10 (s, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.56 (s, 2H), 6.47 (s, 1H) , 4.51 (s, 2H), 4.15 (m, 2H), 2.71 (m, 1H), 1.30 (m, 3H), 1.15 (m, 6H).

Example 52

2-Chloro-W- (2- (4-chlorophenyl) -1-ethyl-1H-benzo [d] ¡m¡dazol-5-¡l) -5 - ((2,2-d¡ met¡lpropane¡lam¡no) methyl) benzam¡da

2- (4-chlorophenyl) -1-ethyl-1H-benzo [d] dazol-5-amine 51 g (50 mg, 0.87 mmol) were added, to do 2-chloro-5 - ((2,2-d¡meth¡lpropano¡lam¡no) methyl) benzo¡co 2a (100 mg, 0.87 mmol), 1-hydroxybenzotr¡azole (25 mg, 0.87 pmol), 1-ethyl-3- (3-dimethylamnopropyl) -carbohydrate hydrochloride (70 mg, 0.367 mmol) in 3 ml of W, A / -d¡met¡lformam¡da successively. The reaction mixture was stirred for 3.5 hours at 40 ° C. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the Title compound, 2-chloro-W- (2- (4-chlorophenyl) -1-ethyl-1H-benzo [d] ¡m¡dazol-5-¡l) -5 - ((2, 2-dimethylpropanolamine) methyl) benzamide 52 (10 mg, 10.7%) as an earthy yellow solid.

MS m / z (ESI): 523.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.39 (br, 1H), 8.18 (d, 2H), 8.10 (s, 1H), 7.70 (s, 1H), 7.66 (d, 1H), 7.58 (m, 2H), 7.56 7.53 (m, 3H), 4.26 (s, 2H), 4.16 (m, 2H), 1.30 (m , 4H), 1.21 (s, 9H).

Example 53

2-Chloro-W- (2- (5-chloropyr¡d¡n-2-¡l) -1H-benzo [d] ¡m¡dazol-5-¡l) -5 - ((2,2 -d¡met¡lpropane¡lam¡no) methyl) benzam¡da

Stage 1

2- (5-Chloropyr¡d¡n-2-¡l) -5-n¡tro-1H-benzo [d] ¡m¡dazole

4-N¡trobenzene-1,2-d¡am¡na 53a (400 mg, 2.6 mmol, 5-chloropyr¡d¡n-2-carbaldehyde 53b (92 mg, 0.65 mmol) and 10 ml of 6N hydrochloric acid were mixed well. The resulting mixture was stirred for 12 hours at 65 ° C. The reaction mixture was filtered, and the filter cake was washed with water (20 ml) and dried to obtain the crude title compound, 2- (5-chloropyr¡d¡n-2-¡l) -5-nitro-1H-benzo [d] Dazole 53c (350 mg) as a yellow solid, which was used in the next stage without further purification.

MS m / z (ESI): 275.1 [M + 1]

Stage 2

2- (5-Chloropyr¡d¡n-2-¡l) -1H-benzo [d] ¡m¡dazol-5-am¡na

2- (5-Chloro-2-p¡r¡d¡l) -5-nitro-1H-benzo [d] ¡m¡dazole 53c (120 mg, 0.44 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of methanol and then added with Raney nickel (100 mg). The reaction mixture was stirred for 12 hours in a hydrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (5-chloropyr¡d¡n-2-¡l) -1H-benzo [d] ¡m¡ dazol-5-amine 53d (110 mg) in the form of a yellow-black oil, which was used in the next stage without additional purification. conal.

MS m / z (ESI): 245.1 [M + 1]

Stage 3

2-Chloro-W- (2- (5-chloropyr¡d¡n-2-¡l) -1H-benzo [d] ¡m¡dazol-5-¡l) -5 - ((2,2 -d¡met¡lpropane¡lam¡no) methyl) benzam¡da

2-Chloro-5 - ((2,2-d, methylpropanolamine) methyl) benzoyl chloride 2b (58 mg, 0.20 mmol) was dissolved in 10 ml of tetrah ¡Drofuran, and then it was added with W, A / -d¡¡soprop¡let¡lam¡na (53 mg, 0.41 mmol) and 2- (5-chloropyr¡d¡n-2- L) -1 H-benzo [d] meddazol-5-amine 53d (50 mg, 0.20 mmol). The resulting mixture was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the Title compound, 2-chloro-W- (2- (5-chloropyr¡d¡n-2-¡l) -1H-benzo [d] ¡m¡dazol-5-¡l) -5- ( (2,2-dimethylpropanolamine) methyl) benzamide 53 (20 mg, 20%) as a light yellow solid. MS m / z (ESI): 496.1 [M + 1]

1H NMR (400MHz, DMSO-da): 810.82 (s, 1H), 8.71 (s, 1H), 8.35 (d, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.57 7.52 (m, 5H), 5.5 (s, 1H), 4.30 (d, 2H), 1.13 (s , 9H).

Example 54

2- (D¡fluoromethyl) -5 - ((2-methylpropane¡lam¡no) methyl) -W- (2- (4- (tr¡fluoromethyl) phen¡l) benzo [ d] t¡azol-6-¡l) n¡cot¡nam¡da

Stage 1

6-Nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] thiazole

Sodium nitrate (27 mg, 0.32 mmol) and 1 ml of concentrated sulfuric acid were mixed, and then 2- (4- (trifluoromethyl) phenol was added l) benzo [d] thiazole 54a (50 mg, 0.18 mmol, prepared according to the method described in "Journal of Molecular Structure, 2012, 1011, 81-93") slowly with temperature keep gives below 75 ° C. After completion of the addition, the reaction mixture was stirred for 1 hour at 70 ° C. The reaction mixture was adjusted to pH 9 with sodium hydroxide solution (50%) and then added with 50 ml of ethyl acetate and 20 ml of water. The organic phase was concentrated under reduced pressure to obtain the crude title compound, 6-nitro-2- (4- (trifluoromethyl) phenyl benzo [d] t¡ azole 54b (58 mg) as a yellow solid, which was used in the next stage without additional purification.

MS m / z (ESI): 325.1 [M + 1]

Stage 2

2- (4- (TrifluorometM) phenyl) benzo [d] thiazol-6-amine

6-Nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] thiazole 54b (58 mg, 0.179 mmol) was dissolved in 5 ml of tetrahydrofuran and 5 ml of methanol and then added with Raney nickel (5 mg) . The reaction mixture was stirred for 20 min under an atmosphere of hydrogen. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4- (tnfluoromethyl) phenyl) benzo [d] thiazol-6-amine 54c (53 mg) as a light yellow solid, which was used in the next step without further purification.

MS m / z (ESI): 295.1 [M + 1]

Stage 3

2- (Difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) -W- (2- (4- (trifluoromethyl) phenyl) benzo [d] thiazol-6-yl) nicotinamide

2- (4- (Trifluoromethyl) phenyl) benzo [d] thiazol-6-amine 54c (53 mg, 0.18 mmol), 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) nicotinic acid were added 1f (49 mg, 0.18 mmol), 1-hydroxybenzotriazole (25 mg, 0.18 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (52 mg, 0.27 mmol) in 5 ml of A /, W-dimethylacetamide. The reaction mixture was stirred for 1 hour at 40 ° C. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - ((2-methylpropanoylamino) methyl) -W- (2- (4- (trifluoromethyl) phenyl) benzo [d] thiazol-6-yl) nicotinamide 54 (20 mg, 20%) as a yellow solid.

MS m / z (ESI): 529.2 [M + 1]

1H NMR (400 MHz, DMSO-da): 810.60 (s, 1H), 8.67 (s, 1H), 8.45 (d, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.89-7.87 (m, 4H), 7.54 (d, 1H), 7.46 (d, 1H), 7.43 (t, 1H), 4.42 ( d, 2H), 3.17-3.16 (m, 1H), 1.05 (s, 6H).

Example 55

2- Chloro-W- (2- (4-chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-yl) -5 - ((2,2-dimethylpropanoylamino) methyl) benzamide

Stage 1

2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-benzo [d] imidazole

2- (4-chlorophenyl) -5-nitro-1H-benzo [d] imidazole 51e (600 mg, 2.2 mmol), iodomethane (0.47 mg, 3.3 mmol) and cesium carbonate (2 , 15 g, 6.6 mmol). The reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of water and filtered. The filter cake was washed with water (20 ml) and dried to obtain the crude title compound, 2- (4-dorofeml) -1-methyl-5-mtro-1H-benzo [d] midazole 55a (0.35 g) as a colored solid yellow, which was used in the next step without further purification.

MS m / z (ESI): 288.2 [M + 1]

Stage 2

2- (4-Chloropheml) -1-methiM H-benzotd Jimidazol-5-amine

2- (4-chlorophenyl) -1-methyl-5-nitro-1H-benzo [d] meddazole 55a (320 mg, 1.11 mmol) was dissolved in 1 ml of tetrahydrofuran and 1 ml of methanol and then added with Raney nickel (50 mg). The reaction mixture was stirred for 12 hours under an atmosphere of hydrogen. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (4-chlorophenyl) -1-methyl-1H-benzo [d] dazol-5-amine 55b ( 112 mg) as a yellow oil, which was used in the next step without further purification.

MS m / z (ESI): 258.1 [M + 1]

Stage 3

2-Chloro-N- (2- (4-chlorophenyl) -1-methyl-1H-benzo [d] ¡m¡dazol-5-¡l) -5 - ((2,2-d¡ met¡lpropane¡lam¡no) methyl) benzam¡da

2- (4-chlorophenyl) -1-methyl-1H-benzo [d] dazol-5-amine 55b (50 mg, 0.19 mmol) was dissolved in 10 ml of tetrahydrofuran, and then with 2-chloro-5 - ((2,2-dimethylpropanolamine) methyl) benzoyl chloride 2b (56 mg, 0.19 mmol), N, N- diisopropylethylamine (52 mg, 0.39 mmol). The resulting mixture was stirred for 2 hours at 65 ° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A and then by HPLC to obtain the title compound, 2-chloro- N- (2- (4-chlorophenyl) -1-methyl-1H-benzo [d] ¡m¡dazol-5-¡l) -5 - ((2,2-d¡methylpropane¡ Lamino) methyl) benzamide 55 (10 mg, 10.1%) as a light yellow solid.

MS m / z (ESI): 509.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 610.37 (br, 1H), 8.16 (d, 2H), 8.12 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.68 (d, 1H), 7.59 (m, 2H), 7.58-7.55 (m, 3H), 4.28 (d, 2H), 3.98 ( s, 3H), 1.23 (s, 9H).

Example 56

2- (D¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -N- (2- (3- (tr¡fluoromet L) phenl) benzo [d] oxazol-5-yl) nicotinamide

Stage 1

5-Nitro-2- (3- (trifluoromethyl) phenyl) benzo [d] oxazole

To a flask, 10 ml of polyphosphoric acid was added and heated to 120 ° C. 3- (Trifluoromethyl) benzoic acid 56a (1.48 g, 7.79 mmol) and 2-amino-4-nitrophenol 56b (1.0 g, 6.49 mmol) were added portionwise. The resulting mixture was stirred for 12 hours at 120 ° C. The reaction mixture was cooled to room temperature and poured into 50 ml of a 1N sodium hydroxide solution. The solution was adjusted to pH 8 ~ 9 with a 1 N sodium hydroxide solution in a ice bath, and then extracted with ethyl acetate (50 mlx3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system B to obtain the title compound, 5-nitro-2- (3- (trifluoromethyl) phenyl) benzo [ d] oxazole 56c (0.26 g, 10%) as a white solid. MS m / z (ESI): 308.9 [M + 1]

Stage 2

2- (3- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine

5-Nitro-2- (3- (trifluoromethyl) phenyl) benzo [d] oxazole 56c (100 mg, 0.3 mmol) was dissolved in 5 ml of tetrahydrofuran and 5 ml of methanol and then added with Raney nickel (30 mg). The reaction mixture was stirred for 1 hour under an atmosphere of hydrogen. The reaction mixture was filtered with celatom. The filtrate was concentrated under reduced pressure to obtain the crude title compound, 2- (3- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 56d (100 mg) as a yellow oil, the which was used in the next step without further purification.

MS m / z (ESI): 279.1 [M + 1]

Stage 3

2- (Difluoromethyl) -5 - (((2-fluoro-2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide

2- (3- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 56d (100 mg, 0.325 mmol), 2- (difluoromethyl) -5 - (((2-fluoro-2-methyl- propanoyl) amino) methyl) nicotinic 14b (94 mg, 0.325 mmol), 1-hydroxybenzotriazole (4.0 mg, 0.03 µmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (125 mg, 0 , 65 mmol) and triethylamine (0.18 ml, 1.3 mmol) in 10 ml of A /, W-dimethylacetamide. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2- (difluoromethyl) -5 - (((2-fluoro -2-methyl-propanoyl) amino) methyl) -W- (2- (3- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 56 (190 mg, 56%) as a solid of light yellow color. MS m / z (ESI): 551.3 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.94 (s, 1H), 8.88 (a, 1H), 8.71 (d, 1H), 8.51 (d, 1H), 8.46 (s, 1H), 8.27 (d, 1H), 8.05 (d, 2H), 7.89-7.97 (m, 1H), 7.84-7.88 (m, 1H), 7.72 (dd, 1H), 7.20 (t, 1H), 4.48 (d, 2H), 1.54 (s, 3H), 1.49 (s, 3H). Example 57

2-Chloro-W-2- (4-chlorophenyl) -3-oxo-isoindolin-5-yl) -5 - ((2,2-dimethylpropanoylamino) methyl) benzamide

Stage 1

2- (4-Chlorophenyl) -6-nitro-isoindolin-1-one

Methyl 2- (bromomethyl) -5-nitro-benzoate 25a (200 mg, 0.73 mmol), 4-chloroaniline (112 mg, 0.88 mmol) and NN-diisopropylethylamine (113 mg, 0.88 mmol) were added ) in 5 ml of ethanol. The reaction mixture was heated to 110 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol (0.5 mlx2) and dried to obtain the title compound, 2- (4-chlorophenyl) -6-nitro-isondolin-1-one 57a (160mg, 76.2%) as a yellow solid.

MS m / z (ESI): 289.0 [M + 1]

Stage 2

6-Amino-2- (4-chlorophenyl) ¡so¡ndol¡n-1-one

2- (4-chlorophenyl) -6-nitro-isondolin-1-one 57a (160 mg, 0.55 mmol) was dissolved in a mixture of 20 ml of tetrahydrofuran and methanol (V : V = 1: 1) and then added with Raney nickel (50 mg). The reaction mixture was stirred for 4 hours under an atmosphere of hydrogen. The reaction mixture was filtered with celatom, and the filtrate was concentrated under reduced pressure to obtain the crude title compound, 6-amno-2- (4-chlorophenyl) -sondolin-1- one 57b (160 mg) as a white solid, which was used in the next step without further purification.

MS m / z (ESI): 259.1 [M + 1]

Stage 3

2-Chloro-N- (2- (4-chlorophenyl) -3-oxo-¡so¡ndol¡n-5-¡l) -5 - ((2,2-d¡meth¡lpropane¡lam¡ no) metal) benzamida

6-Amino-2- (4-chlorophenyl) -sondolin-1-one 57b (80 mg, 0.31 mmol) and triethylamine (0.2 ml, 1.49 mmol) were dissolved in 10 ml of acetonitrile, and then with 2 ml of 2-chloro-5 - ((2,2-dimethylpropanoylamino ^ ethi ^ benzoyl 2b (74 mg, 0.26 mmol) chloride solution in dichloromethane bath) The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with elution system A to obtain the title compound, 2 -chloro-N- (2- ^ -c lo ro fe ml ^ -o xo -iso in do lin ^ -il ^ - ^^ -d im e til propanoylamino ^ eti ^ benzamide 57 (15 mg, 15.9% for two steps) as a light yellow solid.

MS m / z (ESI): 511.2 [M + 1]

1H NMR (400 MHz, DMSO-d6): 810.82 (s, 1H), 8.27 (s, 1H), 8.19 (t, 1H), 7.97 (d, 2H), 7.65 (d, 1H), 7.54 (d, 1H), 7.50 7.53 (m, 3H), 7.46 (s, 1H), 7.37 (d, 1H), 5.01 (s , 2H), 4.30 (s, 2H), 1.13 (s, 9H).

Example 58

2-Chloro-N- (3-oxo-2- (4- (tr¡fluoromethyl) phen¡l) ¡so¡ndol¡n-5-¡l) - 5 - ((2,2-d ¡Met¡lpropano¡l) am¡no) methyl) -benzam¡da

6-Amino-2- (4- (trifluoromethyl) phenyl) -sondolin-1-one 25c (82 mg, 0.28 mmol) and triethylamine (0.2 ml, 1.49 mmol) in 10 ml of dichloromethane, and then added with 10 ml of 2-chloro-5 - ((2,2-dimethylpropanoylamino ^ ethi ^ benzoyl 2b (80 mg, 0.28 mmol) in dichloromethane in an ice bath. The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system to obtain the title compound, 2-chloro-N- (3-oxo ^ - ^ trifluorom ethylfem l ^ so indo lin ^ -il ^ - ^^ - d im ethylpropanoi ^ am ino ^ etiO -benzam ida 58 (4 mg, 2 , 6%) as a light yellow solid.

MS m / z (ESI): 544.1 [M + 1]

1H NMR (400 MHz, DMSO-cfe): 810.84 (s, 1H), 8.30 (d, 1H), 8.17 (d, 3H), 7.87 (d, 1H), 7.82 (s, 2H), 7.70 (d, 1H), 7.55 (d, 1H), 7.47 (s, 1H), 7.38 (d, 1H), 5.08 (s, 2H) , 4.30 (d, 2H), 1.13 (s, 9H)

E je mp lo 59

2- (D¡fluoromethyl) -5 - (((2-fluoro-2-methyl-propano¡l) amino) methyl) -W- (3-oxo-2- (3- (tr¡fluoromethyl) phen¡l) ¡so¡ndol¡n-5-yl) nicotinamide

6-Amino-2- (4- (trifluoromethyl) phenyl) was added sondolin-1-one 25c (100 mg, 0.34 mmol), acid 2- (d¡fluorometh¡l) -5 - (((2-fluoro-2-methyl-propano¡l) am¡no) methyl) n¡cotín¡co 14b (100 mg, 0.34 mmol), 1-ethyl- (3-d¡methylamnopropyl) -carbod¡¡m¡da hydrochloride (130 mg, 0.69 mmol), 1-hydrox¡benzotr Azole (5.0 mg, 37 pmol) and tri-ethylamine (140 µl, 1.03 mmol) in 5 ml of W, A / -dimethylacetamide. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residues were purified by thin layer chromatography (TLC) with an elution system A to obtain the Title compound, 2- (d¡fluoromethyl) -5 - (((2-fluoro-2-methylpropano¡l) amino) methyl) -W- (3-oxo-2- ( 3- (tri-fluoromethyl) phenl) sondolin-5-l) nycotamide 59 (80 mg, 41.5%) as a solid of light yellow color. MS m / z (ESI): 565.1 [M + 1]

1H NMR (400 MHz, DMSO-da): 811.02 (s, 1H), 8.89 (br, 1H), 8.71 (d, 1H), 8.45 (s, 1H), 8.27 (d, 1H), 8.13 (d, 1H), 8.06 (s, 1H), 7.91 (d, 1H), 7.70 (d, 2H), 7.55 (d, 1H) , 7.20 (t, 1H), 5.11 (s, 2H), 4.48 (d, 2H), 1.54 (s, 3H), 1.48 (s, 3H). TEST EXAMPLES BIOLOGICAL TEST

Test Example 1 The nh¡b¡c¡on activity of the present compounds for human mPGES1

The method described in this case is used to determine the inhibition activity of the present compounds for human mPGES1.

I. Materials and appliances

1. K¡t of PGE2 Assay (C¡sb¡o, # 62P2APEB)

2. Prostaglandin H2 (sigma, # P7867-1MG)

3. FlexStat¡on3 Microplate Reader.

II. Experimental procedure

1. Obtaining the membrane proteins of the mPGES1 enzyme

The cell density of HEK-293 F was made at 6 X 105 per ml and the next day the plasmid containing the gene of human mPGES1 using PEI transfection reagent. The cells were grown continuously for 72 hours at 37 ° C with shaking. After centrifuging at 1100 g for 5 minutes, the cells were harvested. After ultrasound treatment in an ice bath and centrifugation at 5000 g for 10 minutes, the supernatant was obtained. The supernatant was centrifuged at 100,000 g for 1 hour to obtain a precipation. The preciptation was resuspended with storage buffer containing 10% glycerine, prepackaged and flash frozen in liquid nitrogen, and stored at -80 ° C. .

2. mPGES1 Enzyme Assay

MPGES1 was diluted with Assay Buffer and added to a plate at 49 μl / well, supplemented with 1 μl of compound (final concentration of each compound set gradient concentrations of 10,000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM and 0.01 nM). 3.8 μl of 20 pg / ml PGH precooled in ice was added to each well after stirring for 30 seconds and incubated for 7 minutes in ice. Next, 53.8 µl of 6 mg / ml ² SnCl was added to each well to interrupt the reaction. The sample was diluted with 1: 400 dilute buffer. 10 µl of dilute sample, 5 µl of PGE2-d2, and 5 µl of cryptoanti-PGE2 were added to a black 384-well plate and incubated at 4 ° C for a night. The HTRF was determined by flexstaton and the IC ⁵⁰ of the compounds was obtained by means of a computerized data processing program.

The inhibition activity of the present compounds on mPGESI is tested by the assay described above. IC ⁵⁰ values are shown below in Table 1.

Table 1 IC inhibition of compound resents on human mPGES1

Conclusion: The present compounds have a significant inhibitory activity on the human mPGESI protein.

Test Example 2 The inhibition activity of the present compounds on guinea pig mPGESI

The method described in this case is used to determine the inhibitory activity of the present compounds for guinea pig mPGES1.

I. Materials and devices

1. PGE2 Assay Kit (Cisbio, # 62P2APEB)

2. Prostaglandin H2 (sigma, # P7867-1MG)

3. FlexStation3 microplate reader.

II. Experimental procedure

1. Obtaining the mPGES1 enzyme membrane proteins

The cell density of HEK-293 F was made at 6 x 105 per milliliter and the next day the plasmid containing the human mPGES1 gene was transferred to them using the PEI transfection reagent. The cells were cultured continuously for 72 hours at 37 ° C with shaking. After centrifuging at 1100g for 5 minutes, the cells were harvested. After sonication in an ice bath and centrifugation at 5000 g for 10 minutes, the supernatant was obtained. The supernatant was centrifuged at 100,000 g for 1 hour to obtain precipitation. The precipitation was resuspended with storage buffer containing 10% glycerin, prepackaged and flash frozen in liquid nitrogen, and stored at -80 ° C.

2, mPGES1 Enzyme Assay

MPGES1 was diluted with assay buffer and added to a plate at 49 µl / well, supplemented with 1 µl of compound (final concentration of each compound at seven gradient concentrations of 10,000 nM, 1000 nM, 100 nM, 10 nM, 1 nM , 0.1 nM and 0.01 nM). To each well, 3.8 µl of ice pre-cooled 20 pg / ml PGH was added after shaking for 30 seconds and incubated for 7 minutes on ice. Next, 53.8 µl of 6 mg / mh SnCl was added to each well to stop the reaction. The sample was diluted with buffer diluted 1: 400.

10 µl of diluted sample, 5 µl of PGE2-d2 and 5 µl of cryptate anti-PGE2 were added to a black 384-well plate and incubated at 4 ° C overnight. The HTRF was determined by flexstation and the IC ⁵⁰ of the compounds was obtained by a data processing computer program. The inhibitory activity of the present compounds on mpGES1 is tested by the assay described above. IC ⁵⁰ values are shown below in Table 2.

Ta l 2 L I inhi i i n l r n m r mP E 1 ya

Conclusion: The present compounds have significant activity on guinea pig mPGES1 protein. Test Example 3. The inhibition activity of the present compounds on the secretion of PGE2 by A549 cells under stimulation of IL-1p

The method described in this case is used to determine the inhibitory activity of the present compounds on the secretion of PGE2 by A549 cells under stimulation of IL-1 p.

I. Materials and devices

1. PGE2 Assay Kit (Cisbio, # 62P2APEB)

2. IL-1 p (Peprotech, # AF-200-01B)

3. Cell line: A549 (ATCC: CCL-185)

4. FlexStation3 microplate reader.

II. Experimental procedure

On the first day, A549 cells were inoculated into a 96-well plate at 40,000 / well. On the second day, the culture medium was removed from the 96-well plate and then 90 µl of the compounds diluted with culture medium were added (the concentration of each compound at seven gradient concentrations of 11111 nM, 11111 nM, 111 nM, 11.11 nM, 1.11 nM, 0.11 nM and 0.011 nM). The cells were incubated for 30 minutes at 37 ° C in an incubator, and then IL-1 p was added to the final concentration of 0.2 ng / ml. The cells were then incubated for another 24 hours at 37 ° C. On the third day, 10 µl of supernatant, 5 µl of PGE2-d2 and 5 µl of anti-PGE2 cryptate were added in a black 384-well plate and then incubated at 4 ° C overnight. The HTRF was determined by flexstation and the IC ⁵⁰ of the compounds was obtained by a data processing computer program.

The inhibitory activity of the present compounds on PGE2 secretion by A549 cells under IL-1p stimulation is determined by the assay described above. IC ⁵⁰ values are shown below in Table 3.

Table 3 IC 50 of the inhibition activity of the present compounds on PGE2 secretion by A549 cells under IL-1 stimulation

Conclusion: The present compounds have significant inhibitory activity on PGE2 secretion by A549 cells under IL-1p stimulation.

PHARMACOKINETICS TEST

Test Example 4 The pharmacokinetic assay of the present compounds

1. Summary

SD rats were used as test animals. The drug concentration in plasma at different time points was determined by LC / MS / MS after the administration of the compounds of Example 8, Example 11, Example 14, Example 17, Example 20, Example 27, Example 33, Example 35, Example 36, Example 37 and Example 48 to rats. The pharmacokinetic behavior of the present compounds was studied and evaluated in rats.

2. Protocol

2.1 Samples

Compounds of Example 8, Example 11, Example 14, Example 17, Example 20, Example 27, Example 33, Example 35, Example 36, Example 37, and Example 48.

2.2 Test animals

44 healthy adult Sprague-Dawley (SD) rats, half male and half female, which were purchased from SINO-BRITSH SIPPR / BK LAB. ANIMAL LTD., CO, with Certification No.: SCXK (Shanghai) 2008-0016, they were divided into 11 groups, 4 rats for each group.

2.3 Preparation of test compounds

The appropriate amount of test compounds was weighed out and mixed with 25 µl of Tween 80 and Labrasol to prepare a 0.6 mg / ml suspension by sonication.

2.4 Administration

After an overnight fast, 44 SD rats, half male and half female, were divided into 11 groups and administered intragastrically a dose of 5.0 mg / kg and an administration volume of 10 ml / kg.

3. Procedure

Blood samples (0.1 ml) were taken from the orbital sinus, before administration and at 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h , 11.0 h and 24.0 h after administration. Samples were stored in EDTA anticoagulation tubes, and centrifuged for 5 minutes at 3,500 rpm to separate blood plasma. Plasma samples were stored at -20 ° C. Rats were given food 2 hours after administration.

The plasma concentration of test compounds in rats after intragastric administration was determined by LC-MS / MS. The linearity of the method is 5.00-2000 ng / ml and 1.00-2000 ng / ml, and the minimum quantification is 5.00 ng / ml and 1.00 ng / ml. Plasma samples were analyzed after pretreatment by protein precipitation.

4. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the present compounds are shown below.

continuation

Conclusion: The present compounds have good pharmacokinetic data and a significant pharmacokinetic absorption effect.

Claims (17)

1. A compound of general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where: ring P is selected from a five-membered heteroaryl and a five-membered heterocyclyl; ring Q is selected from phenyl and pyridinyl; A, B or Y is selected from -CH- and N; R1 is selected from alkyl and cycloalkyl, wherein said alkyl or cycloalkyl is further optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, and haloalkyl; R2 is selected from halogen and haloalkyl; R3 are identical or different, and each is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, and oxo, wherein said alkyl, cycloalkyl, and heterocyclyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, alkoxy, and alkyl; R4 is selected from phenyl and pyridinyl, wherein said phenyl and pyridinyl are each further optionally substituted by one or more groups selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein said haloalkyl is preferably trifluoromethyl; s is an integer between 0 to 3; t is 1. 2. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1, is a compound of formula ( II), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where: X is selected from -CH- and N; ring P, A, B, Y, s, t and R1 ~ R4 are as defined in claim 1. 3. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1, is a compound of formula ( III), formula (IV) or formula (V), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where: X is selected from -CH- and N; E, G, and W are each independently selected from CRa, NRb, N, O, and S; each of Ra and Rb is independently selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are each further optionally substituted by one or more groups selected from the group that consists of halogen, hydroxy, alkoxy, and alkyl; Y A, B, Y, t, R1 ~ R2 and R4 are as defined in claim 1. 4. A compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1, is a compound of the formula ( VI), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where: X is selected from -CH and N; Rb is selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are further each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy and alkyl; Y A, B, Y, t, R1 ~ R2 and R4 are as defined in claim 1. 5. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1, is a compound of the formula ( VII), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof:

where: X is selected from -CH and N; Rb is selected from hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are further each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy and alkyl; R8 is selected from halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl, wherein said haloalkyl is preferably trifluoromethyl; Y A, B, Y, R1 ~ R2 is as defined in claim 1. 6. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 5, where A, B and Y are -CH-. 7. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 5, where one of A, B and Y is N, the other two are -CH-. 8. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claims 1 or 2, wherein said groups

are selected from:

R3 and R4 are as defined in claim 1. 9. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein said R1 is selected between tertiary butyl, isopropyl,

10. The compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 9, wherein said compounds are selected from:

11. A process for preparing the compound of formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1, comprising a stage of:

reacting a compound of formula (IA) or salts thereof with a compound of formula (IB) to give a compound of formula (I); where: Rc is selected from hydroxy and halogen; ring P, ring Q, A, B, Y, s, t and R1 ~ R4 are as defined in claim 1. 12. A compound of formula (IA), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof,

comprising the following groups:

where: R3 is selected from hydrogen, alkyl, and heterocyclyl, wherein said alkyl, furthermore, is optionally substituted by one or more alkoxy; R4 is selected from phenyl and pyridinyl, wherein said phenyl or pyridinyl is substituted with one or more groups selected from the group consisting of halogen and haloalkyl, wherein said haloalkyl is preferably trifluoromethyl; R4 is preferably phenyl, wherein said phenyl is further substituted by a halogen or haloalkyl; as long as: when the general formula (IA) is the following groups:

R3 is selected from hydrogen and alkyl, wherein said alkyl is further optionally substituted by one or more groups selected from alkoxy and heterocyclyl; R4 is phenyl, wherein said phenyl is further substituted by a haloalkyl, wherein said haloalkyl is preferably trifluoromethyl; or R3 is heterocyclyl; R4 is phenyl, wherein said phenyl is further substituted by a halogen or haloalkyl. 13. A compound selected from:

14. A pharmaceutical composition comprising therapeutically effective amount of the compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof according to claim 1 and a pharmaceutically acceptable carrier, diluents, or excipient. 15. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 10, or the composition pharmaceutical according to claim 14, for use as a medicament for the treatment of diseases mediated by microsomal prostaglandin E synthase 1. 16. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 10, or the composition pharmaceutical according to claim 14, for use as a medicament for the inhibition of microsomal prostaglandin E synthase 1. 17. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 14, for use as a medicament for the treatment and / or prevention of diseases or disorders, wherein said diseases or disorders are selected from the group consisting of inflammation, pain, cancer, diabetes and diabetic complications, or neurodegenerative disorders, preferably inflammation or pain, more preferably osteoarthritis, rheumatoid arthritis, bursitis, ankylosing spondyloarthritis, or pain associated with any one of these diseases or disorders.